JP2005301523A - Apparatus and method for predicting vaccine candidate partial sequence, apparatus and method for predicting mhc-binding partial sequence, program and recording medium - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an apparatus and a method for predicting vaccine candidate partial sequence, which predict a partial sequence constituting vaccine by activating a T cell, from protein amino acid sequence information, and also to provide program, recording medium, etc. thereof. <P>SOLUTION: The vaccine candidate partial sequence prediction apparatus acquires object sequence information related to an object sequence of protein or an amino acid sequence of bioactive polypeptide. From the object sequence information, there are predicted a uncut partial sequence which is not cut by proteome or a proteolytic enzyme existent in a lysosome, an MHC-binding partial sequence capable of binding with a particular major histocompatibility antigen, and a non-self recognition partial sequence which is not recognized as self and a non-mutagenic partial sequence in which mutation is hard to enter. Based on the predicted uncut partial sequence, MHC-binding partial sequence, non-self recognition partial sequence and/or non-mutagenic partial sequence, the vaccine candidate partial sequence effective as vaccine is predicted. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a vaccine candidate partial sequence prediction apparatus, a vaccine candidate partial sequence prediction method, a program, and a recording medium, and in particular, an amino acid sequence that can activate a T cell from an amino acid sequence of a protein or a biologically active polypeptide (peptide The present invention relates to a vaccine candidate partial sequence prediction apparatus, a vaccine candidate partial sequence prediction method, a program, and a recording medium that can predict an amino acid sequence to be a vaccine with high accuracy by predicting (sequence). The present invention also relates to an MHC binding partial sequence prediction apparatus, an MHC binding partial sequence prediction method, a program, and a recording medium, and in particular, from a protein or a bioactive polypeptide amino acid sequence, a specific major histocompatibility antigen (MHC: Major). The present invention relates to an MHC-binding partial sequence prediction apparatus, an MHC-binding partial sequence prediction method, a program, and a recording medium that can predict an amino acid sequence (peptide sequence) that can be combined with Histocompatibility Complex) with high accuracy.

  “Peptide vaccine” refers to a pharmaceutical comprising a peptide as a main structure, which is expected to have an indirect therapeutic effect or preventive effect by regulating the immune function of the human body.

  Here, the immune function of the human body will be briefly described. First, when a human body is exposed to a pathogen such as a virus or a bacterium, a protein derived from the pathogen is decomposed in a human cell, and binds to a human leukocyte antigen (HLA) molecule, which is a human MHC. Presented as an antigen outside. When T lymphocyte cells present in blood and regulating immune function recognize a protein (peptide) derived from a pathogen bound to an HLA molecule, immune functions including proliferation of cytotoxic T lymphocyte cells Increases. Thereby, when the pathogen enters the human body again, the pathogen can be quickly eliminated from the human body. Vaccines utilize the immune function of the human body and use detoxified pathogens.

  However, serious side effects have often been reported in vaccines made from detoxified pathogens and the like.

  Therefore, if a peptide fragment derived from a pathogen that binds to an HLA molecule in advance can be predicted, the peptide fragment can be a highly effective and promising candidate substance as a peptide vaccine preparation with few side effects.

  Specifically, for example, it is possible to predict and propose vaccine candidate peptides very quickly even for emerging infectious diseases such as SARS.

  In addition, the immune system eliminates cancer cells by, for example, recognizing protein fragments inherent to cancer cells and enhancing immune functions including cytotoxic T cells against cancer cells. For example, if a peptide fragment unique to a cancer cell that binds to an HLA molecule can be predicted in advance, the peptide fragment is a highly effective candidate with no side effects and a promising candidate substance as an anticancer agent. It can be. In fact, for leukemia and the like, cancer immunotherapy by administration of a cancer antigen peptide has been attempted, and some have achieved good results.

  In addition, for example, symptoms in allergic diseases represented by hay fever, atopy, asthma, rheumatism, etc. appear due to abnormally enhanced immune functions against allergens (antigens) such as pollen, and thus bind to HLA molecules. It is said that the entire immune function can be induced into an immunological tolerance (anazy) state against the allergen by successfully selecting a peptide derived from the allergen. That is, if an allergen-derived peptide fragment that binds to an HLA molecule in advance can be predicted, the peptide fragment can be a promising candidate substance as an antiallergic preparation that is extremely efficient and has few side effects.

  As described above, peptide fragments that activate T cells predicted from the sequence information of proteins related to various diseases have the potential to become pharmaceuticals. Very useful.

  Here, conventionally, various methods for predicting vaccine candidates in silico from peptide sequences have been proposed.

  First, the most common method is a method using sequence information of a peptide that is known to bind experimentally. In this method, commonness of peptides to be combined is extracted from sequence information of peptides known to be experimentally combined by using machine learning such as a neural network. That is, this method is based on the idea that peptides having the above-mentioned commonality among proteins also bind to MHC. And there is a report (for example, refer nonpatent literature 1) that the prediction of the T cell epitope of hepatitis C was implemented, for example until now.

  According to this method, if information on peptides that bind to MHC is abundant, it is possible to predict vaccine candidate peptides with high accuracy.

  Further, as a method that does not depend on a known binding peptide, there is a method of actually calculating the interaction with the peptide using the structure of MHC. And there is a report (for example, refer nonpatent literature 2) that the complex of HLA-DRB1 * 0101 and a peptide was predicted with high precision, for example until now.

  According to this method, it is possible to predict a vaccine candidate peptide based on the predicted complex without requiring information on a peptide whose binding is known.

Protein Sci. , 12, p. 1007-1017, 2003 Proteins: Structure, Function, and Bioinformatics, Volume 54, Issue 3, p. 534-556

  However, in the method using the sequence information of the peptide that is known to bind experimentally as described above (Non-patent Document 1 and the like described above), if there is abundant information on the peptide that binds to MHC, high-precision prediction is possible. Although it is possible, there is a problem in that the prediction accuracy is insufficient for many types of MHC because there is little information on the peptides to be bound in many MHCs at present.

  In addition, the above-described methods that do not depend on a known binding peptide (Non-Patent Document 2 described above) have the advantage that the binding peptide is known, but the problem is that the calculation time becomes enormous. There is a point.

  Viruses are also thought to escape immune attack by causing mutations in antigenic determinants. For this reason, even if a peptide vaccine having a sequence that is prone to mutation is developed, it is expected that the effect will soon be lost due to the frequent mutation of the virus. That is, a peptide vaccine having a sequence with less mutation is considered to have a sustained effect.

  However, there is a problem that there is no technique for designing a peptide vaccine in consideration of how to introduce a mutation.

  The present invention has been made in view of the above problems, and predicts an amino acid sequence (peptide sequence) capable of activating T cells from an amino acid sequence of a protein or a physiologically active polypeptide, thereby providing a vaccine. It is an object of the present invention to provide a vaccine candidate partial sequence predicting apparatus, a vaccine candidate partial sequence predicting method, a program, and a recording medium that can predict an amino acid sequence to be highly accurate. In addition, the present invention predicts with high accuracy an amino acid sequence (peptide sequence) capable of binding to a specific major histocompatibility complex (MHC) from the amino acid sequence of a protein or bioactive polypeptide. It is an object of the present invention to provide an MHC binding partial sequence prediction apparatus, an MHC binding partial sequence prediction method, a program, and a recording medium.

  Peptide vaccines are presented as antigens by binding to MHC molecules without being decomposed in cells such as humans, and T lymphocyte cells recognize peptides derived from pathogens bound to HLA molecules. is necessary. Furthermore, the peptide vaccine is also required to be adjusted so as not to respond to the self-peptide in order to maintain immune tolerance regarding self, that is, not to be self.

  The present invention satisfies the following four conditions: 1) resistance to proteolytic enzymes or proteosomes present in lysosomes, 2) binding to MHC, 3) not recognized as self-peptides, and 4) difficult to enter mutations. This is based on the idea that peptides are effective as vaccines.

  Therefore, in order to solve the above-described problems and achieve the object, the vaccine candidate partial sequence prediction apparatus according to claim 1 is an object that is information on an object sequence that is an amino acid sequence of an object protein or bioactive polypeptide. A target sequence obtaining means for obtaining sequence information; and the amino acid sequence that is not cleaved by a protease or proteosome present in lysosome from the target sequence information obtained by the target sequence obtaining means, The amino acid sequence capable of binding to a specific major histocompatibility antigen from the target sequence information obtained by the target sequence obtaining means and the non-cleavable partial sequence predicting means for predicting the non-cleavable partial sequence which is a partial sequence MHC that predicts an MHC binding partial sequence that is a partial sequence of the target sequence A non-self-recognizing partial sequence that is a non-self-recognized partial sequence that is not recognized as self from the target sequence information acquired by the combined partial sequence prediction unit and the target sequence acquisition unit From the target sequence information acquired by the self-recognizing partial sequence predicting means and the target sequence acquiring means, the non-mutated partial sequence that is not easily mutated and is a partial sequence of the target sequence is predicted. Non-mutated partial sequence predicting means, the non-cut partial sequence predicted by the non-cut partial sequence predicting means, the MHC binding partial sequence predicted by the MHC binding partial sequence predicting means, and the non-self-recognizing partial sequence Predicted by the non-self-recognizing partial sequence predicted by the predicting means and / or predicted by the non-mutated partial sequence predicting means. It was based on the non-mutated subsequences, characterized in that a vaccine candidate subsequence predicting means for predicting a vaccine candidate subsequence is a valid the amino acid sequence as a vaccine.

  According to this apparatus, target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide, is obtained, and a proteolytic enzyme or proteosome present in the lysosome is obtained from the obtained target sequence information. An amino acid sequence that is not cleaved by the target sequence and that is capable of binding to a specific major histocompatibility antigen from the target sequence information obtained by predicting a non-cleaved partial sequence that is a partial sequence of the target sequence. Predicting an MHC-binding partial sequence that is a partial sequence of the target sequence, and predicting a non-self-recognizing partial sequence that is an amino acid sequence that is not recognized as self from the acquired target sequence information and that is a partial sequence of the target sequence; From the obtained target sequence information, it is an amino acid sequence that is difficult to mutate, and is a partial sequence of the target sequence. Based on the predicted non-mutated partial sequence, the predicted MHC binding partial sequence, the predicted non-self-recognizing partial sequence, and / or the predicted non-mutated partial sequence. Because the vaccine candidate partial sequence, which is an amino acid sequence effective as a vaccine, is predicted, from the target sequence information, 1) resistant to proteolytic enzymes or proteosomes present in lysosomes, 2) bound to MHC, and 3) self The vaccine candidate partial sequence optimal as a vaccine that satisfies the four conditions of being unrecognized as a peptide and 4) difficult to enter a mutation and capable of activating T cells can be predicted efficiently and with high accuracy.

  The vaccine candidate partial sequence prediction apparatus according to claim 2 is the vaccine candidate partial sequence prediction apparatus according to claim 1, wherein the non-cleavable partial sequence prediction means is a site cleaved by the proteolytic enzyme. Stored by the cleavage site-containing sequence storage means for storing the cleavage site-containing sequence information, which is information relating to the cleavage site-containing sequence, which is the amino acid sequence including several residues before and after the enzyme cleavage site, and the cleavage site-containing sequence storage means A cleavage site-containing sequence amino acid appearance frequency calculating means for calculating cleavage site-containing sequence amino acid appearance frequency information, which is information relating to the appearance frequency of amino acids at positions corresponding to each amino acid residue in the cleavage site-containing sequence, and the cleavage site containing Based on the cleavage site-containing sequence amino acid appearance frequency information calculated by the sequence amino acid appearance frequency calculation means Obtained by the target sequence acquisition means based on the cleavage site-containing sequence score calculation means for calculating the cleavage site-containing sequence score information and the cleavage site-containing sequence score information calculated by the cleavage site-containing sequence score calculation means. A cleavage site-containing sequence length partial sequence score calculating means for calculating the cleavage site-containing sequence length partial sequence score information corresponding to each partial sequence obtained by dividing the target sequence into the length of the cleavage site-containing sequence, and the cleavage site The enzyme cleavage site is determined based on the cleavage site-containing sequence length partial sequence score information calculated by the contained sequence length partial sequence score calculation means, and the partial sequence cleaved at the enzyme cleavage site is used as the non-cleavable partial sequence It further comprises score-based non-cutting partial sequence prediction means for prediction.

  This more specifically shows one example of the non-cut partial sequence predicting means. According to this apparatus, the non-cleavable partial sequence predicting means includes a cleavage site-containing sequence that is information on a cleavage site-containing sequence that is an amino acid sequence including several residues before and after the enzyme cleavage site, which is a site cleaved by a proteolytic enzyme. Information is stored, the cleavage site-containing sequence amino acid appearance frequency information, which is information about the appearance frequency of amino acids at positions corresponding to each amino acid residue in the stored cleavage site-containing sequence, is calculated, and the calculated cleavage site-containing sequence Each partial sequence obtained by calculating cleavage site-containing sequence score information based on amino acid appearance frequency information and dividing the obtained target sequence into the length of the cleavage site-containing sequence based on the calculated cleavage site-containing sequence score information Cleaving site-containing sequence length partial sequence score information corresponding to the And the partial sequence cleaved at the enzyme cleavage site is predicted as a non-cleavable partial sequence. Based on the frequency analysis of the cleavage site-containing sequence, the enzyme cleavage site by the proteolytic enzyme or proteosome present in the lysosome is determined. By predicting with high accuracy, it is possible to predict the non-cut partial sequence efficiently and with high accuracy.

  The vaccine candidate partial sequence prediction apparatus according to claim 3 is the vaccine candidate partial sequence prediction apparatus according to claim 1, wherein the non-cleavable partial sequence prediction means is a site cleaved by the proteolytic enzyme. From the cleavage site sequence storage means for storing the cleavage site sequence information, which is information relating to the cleavage site sequence, which is the amino acid sequence of the enzyme cleavage site, and from the cleavage site sequence information stored by the cleavage site sequence storage means, a known cleavage A cleavage site motif sequence extracting means for extracting a site motif sequence, and a motif for the target sequence acquired by the target sequence acquisition means using the cleavage site motif sequence extracted by the cleavage site motif sequence extraction means Search for the enzyme cleavage site in the target sequence by executing the search, and the search score A cleavage site motif search means for obtaining a certain cleavage site search score information, and determining the enzyme cleavage site of the target sequence based on the cleavage site search score information obtained by the cleavage site motif search means, and the enzyme cleavage It further includes a motif search reference non-cutting partial sequence predicting means for predicting a partial sequence cut at a site as the non-cutting partial sequence.

  This more specifically shows one example of the non-cut partial sequence predicting means. According to this apparatus, the non-cleavable partial sequence predicting means stores and stores the cleavage site sequence information that is information on the cleavage site sequence that is the amino acid sequence of the enzyme cleavage site that is the site cleaved by the proteolytic enzyme. Extracts a known cleavage site motif sequence from the cleavage site sequence information, searches the target sequence for the enzyme cleavage site using the extracted cleavage site motif sequence, and searches for the enzyme cleavage site in the target sequence. Obtain the cleavage site search score information that is the score at the time, determine the enzyme cleavage site of the target sequence based on the obtained cleavage site search score information, and the partial sequence cleaved at the enzyme cleavage site as a non-cleaved partial sequence Based on the motif search for the target sequence, the proteolytic enzyme or proteosome present in the lysosome Uncut partial sequences can be predicted efficiently high precision by predicting the that enzyme cleavage sites with high precision.

  In addition, the vaccine candidate partial sequence predicting apparatus according to claim 4 is the vaccine candidate partial sequence predicting apparatus according to any one of claims 1 to 3, wherein the MHC binding partial sequence predicting means is the specific A major histocompatibility antigen determining means for determining the type of major histocompatibility antigen, and a number of residues remaining before and after the MHC binding site which is a site to bind to the major histocompatibility antigen determined by the major histocompatibility antigen determination means. MHC binding site-containing sequence storage means for storing MHC binding site-containing sequence information that is information relating to the MHC binding site-containing sequence that is the amino acid sequence including the group; and the MHC binding stored by the MHC binding site-containing sequence storage means MHC binding site-containing sequence that is information regarding the frequency of occurrence of amino acids at positions corresponding to each amino acid residue in the site-containing sequence Based on the MHC binding site-containing sequence amino acid appearance frequency calculating means for calculating the amino acid appearance frequency information, and the MHC binding site-containing sequence amino acid appearance frequency information calculated by the MHC binding site-containing sequence amino acid appearance frequency calculating means. Based on the MHC binding site-containing sequence score calculation means calculated by the MHC binding site-containing sequence score calculation means, the target sequence acquisition means calculates the binding site-containing sequence score information. MHC binding site-containing sequence length partial sequence score calculating means for calculating MHC binding site-containing sequence length partial sequence score information corresponding to each partial sequence obtained by dividing the obtained target sequence into the length of the MHC binding site-containing sequence; The MHC calculated by the MHC binding site-containing sequence length partial sequence score calculation means A scoring reference MHC binding partial sequence predicting means for determining the MHC binding site based on the combined site-containing sequence length partial sequence score information and predicting the partial sequence including the MHC binding site as the MHC binding partial sequence; It is characterized by that.

  This shows one example of the MHC binding partial sequence predicting means more specifically. According to this apparatus, the MHC binding subsequence prediction means determines the type of a specific major histocompatibility antigen, and determines several residues before and after the MHC binding site, which is the site that binds to the determined major histocompatibility antigen. Information on the appearance frequency of amino acids at positions corresponding to each amino acid residue in the stored MHC binding site-containing sequence; MHC binding site-containing sequence amino acid appearance frequency information is calculated, MHC binding site-containing sequence amino acid appearance frequency information is calculated based on the calculated MHC binding site-containing sequence amino acid appearance frequency information, and the calculated MHC binding site-containing sequence score is calculated MHC binding corresponding to each partial sequence obtained by dividing the obtained target sequence into the length of the MHC binding site-containing sequence based on the information The position-containing sequence length partial sequence score information is calculated, the MHC binding site is calculated based on the calculated MHC binding site-containing sequence length partial sequence score information, and the partial sequence including the MHC binding site is predicted as the MHC binding partial sequence Therefore, based on the amino acid frequency analysis of known MHC binding site-containing sequences corresponding to various major histocompatibility antigens, by accurately predicting the MHC binding site binding to a specific major histocompatibility antigen, An MHC binding partial sequence can be predicted efficiently and with high accuracy.

  Further, the vaccine candidate partial sequence predicting device according to claim 5 is the vaccine candidate partial sequence predicting device according to any one of claims 1 to 3, wherein the MHC binding partial sequence predicting means is the specific Major histocompatibility antigen determining means for determining the type of major histocompatibility antigen, and the amino acid sequence of the MHC binding site which is a site binding to the major histocompatibility antigen determined by the major histocompatibility antigen determination means MHC binding site sequence storage means for storing MHC binding site sequence information, which is information related to the MHC binding site sequence, and a known MHC binding site from the MHC binding site sequence information stored by the MHC binding site sequence storage means. MHC binding site motif sequence extracting means for extracting a motif sequence and the above MHC binding site motif sequence extracting means The MHC binding site in the target sequence is searched by performing a motif search on the target sequence acquired by the target sequence acquisition means using the MHC binding site motif sequence that has been issued. MHC binding site motif search means for acquiring MHC binding site search score information as a score, and determining the MHC binding site based on the MHC binding site search score information acquired by the MHC binding site motif search means, Motif search reference MHC binding partial sequence predicting means for predicting the partial sequence including an MHC binding site as the MHC binding partial sequence is further provided.

  This shows one example of the MHC binding partial sequence predicting means more specifically. According to this apparatus, the MHC binding subsequence prediction means determines the type of a specific major histocompatibility antigen, and the MHC that is the amino acid sequence of the MHC binding site that is the site that binds to the determined major histocompatibility antigen. Stores MHC binding site sequence information, which is information related to the binding site sequence, extracts a known MHC binding site motif sequence from the stored MHC binding site sequence information, and obtains it using the extracted MHC binding site motif sequence A motif search is performed on the target sequence thus obtained to search for an MHC binding site in the target sequence, MHC binding site search score information that is a score at the time of search is obtained, and the acquired MHC binding site search score information is obtained. MHC binding site is determined based on this, and a partial sequence including the MHC binding site is predicted as an MHC binding partial sequence. Detecting motifs using known MHC binding site sequences corresponding to histocompatibility antigens, and predicting MHC binding sites binding to specific major histocompatibility antigens with high accuracy based on the motif search Thus, the MHC binding partial sequence can be predicted efficiently and with high accuracy.

  Further, the vaccine candidate partial sequence predicting device according to claim 6 is the vaccine candidate partial sequence predicting device according to any one of claims 1 to 3, wherein the MHC binding partial sequence predicting unit is configured to perform the specific operation. A major histocompatibility antigen determining means for determining the type of major histocompatibility antigen, and a major histocompatibility antigen sequence which is the amino acid sequence of the major histocompatibility antigen determined by the major histocompatibility antigen determination means MHC sequence acquisition means for acquiring information of major histocompatibility antigen sequence information, and the main histocompatibility antigen determined by the main histocompatibility antigen determination means as the target sequence acquired by the target sequence acquisition means MHC long partial sequence creating means for creating an MHC long partial sequence by dividing into lengths corresponding to the above types, and the MHC long partial sequence creating means A complex three-dimensional structure predicting means for predicting complex three-dimensional structure information based on each of the MHC long partial sequences prepared by the MHC sequence obtaining means and the major histocompatibility antigen sequence obtained by the MHC sequence obtaining means; An interacting amino acid that is information on the set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence based on the complex three-dimensional structure information predicted by the structure prediction means Affinity information, which is information relating to the affinity between the amino acid set included in the interaction amino acid determination means determined by the interaction amino acid determination means and the interaction amino acid determination means determined by the interaction amino acid determination means, Affinity calculation means for calculating statistically using structural information, and all the above-mentioned calculated by the affinity calculation means Affinity sum calculation means for calculating the sum of the affinity information between the groups of mino acids, and based on the sum of the affinity information calculated by the affinity sum calculation means, the MHC length subsequence and the main tissue compatibility And an affinity reference MHC binding partial sequence predicting means for predicting the MHC binding partial sequence by evaluating the affinity with a sex antigen.

  This shows one example of the MHC binding partial sequence predicting means more specifically. According to this apparatus, the MHC binding partial sequence predicting means determines the type of a specific major histocompatibility antigen, and is information on the major histocompatibility antigen sequence that is the amino acid sequence of the determined major histocompatibility antigen. The major histocompatibility antigen sequence information is obtained, the obtained target sequence is divided into lengths corresponding to the determined major histocompatibility antigen types, MHC length subsequences are created, and each created MHC Based on the long partial sequence and the obtained major histocompatibility antigen sequence, complex tertiary structure information is predicted, and based on the predicted complex tertiary structure information, the MHC long partial sequence and the major histocompatibility antigen sequence are Information on interaction amino acid information that is information on amino acid pairs interacting with each other, and information on affinity between amino acid sets included in the determined interaction amino acid information. Affinity information is statistically calculated using the three-dimensional structure information of known proteins, the sum of affinity information between all calculated amino acid pairs is calculated, and based on the calculated sum of affinity information Thus, the MHC binding partial sequence is predicted by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen. Therefore, the complex three-dimensional structure with MHC is not dependent on the information of the known binding peptide. Based on the statistically calculated affinity, the MHC binding partial sequence that binds to and interacts with a specific major histocompatibility antigen can be predicted with high speed and high accuracy.

  In addition, the vaccine candidate partial sequence prediction apparatus according to claim 7 is the vaccine candidate partial sequence prediction apparatus according to claim 6, wherein the MHC long partial sequence creation means is the purpose acquired by the target sequence acquisition means. A slide splitting means for creating the MHC long partial sequence by splitting the sequence into the length corresponding to the type of the major histocompatibility antigen while sliding the amino acid residue from the top one by one; Features.

  This more specifically shows one example of the MHC length partial sequence creating means. According to this apparatus, the MHC length partial sequence creating means divides the acquired target sequence into lengths corresponding to the types of major histocompatibility antigens while sliding the amino acid residues one by one from the beginning. Since the partial sequence is created, an MHC length partial sequence that may be divided can be created without omission.

  The vaccine candidate partial sequence prediction apparatus according to claim 8 is the vaccine candidate partial sequence prediction apparatus according to claim 6 or 7, wherein the length corresponding to the type of the major histocompatibility antigen is 8 The number of residues is ˜18.

  This is a more specific example of the length corresponding to the type of major histocompatibility antigen. According to this apparatus, since the length corresponding to the type of major histocompatibility antigen is 8 to 18 residues, for example, it is 8 to 12 residues for MHC class I, and MHC class II On the other hand, since the number of residues can be 12-18, an MHC length partial sequence having an optimum length corresponding to each MHC type can be prepared.

  The vaccine candidate partial sequence predicting device according to claim 9 is the vaccine candidate partial sequence predicting device according to any one of claims 6 to 8, wherein the MHC binding partial sequence predicting means is the main tissue compatible MHC binding, which is information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen determined by the sex antigen determination means and each amino acid residue of the major histocompatibility antigen sequence MHC binding amino acid residue distance value storage means for storing amino acid residue distance value information is further provided, wherein the affinity calculation means stores the affinity information by the MHC binding amino acid residue distance value storage means. Statistical potential using the MHC-binding amino acid residue distance value information and / or the three-dimensional structure information of the known protein And further comprising a distance value based affinity calculation means for calculating using.

  This more specifically shows one example of the MHC binding partial sequence predicting means and the affinity calculating means. According to this apparatus, the MHC binding partial sequence predicting means calculates the distance value between each amino acid residue of the amino acid sequence that binds to the determined major histocompatibility antigen and each amino acid residue of the major histocompatibility antigen sequence. MHC binding amino acid residue distance value information, which is information relating to the information, and the affinity calculation means stores the affinity information, the stored MHC binding amino acid residue distance value information, and / or the three-dimensional structure information of the known protein. Since it is calculated using the statistical potential using, it does not depend on the information of the known binding peptide, and it is calculated using the statistical potential using the distance between MHC-binding amino acid residues from the 3D complex structure with MHC. Based on the determined affinity, MHC binding subsequences that bind to and interact with specific major histocompatibility antigens can be predicted at high speed and with high accuracy.

  The vaccine candidate partial sequence predicting device according to claim 10 is the vaccine candidate partial sequence predicting device according to any one of claims 1 to 3, wherein the MHC-binding partial sequence predicting means is the specific Main histocompatibility antigen determining means for determining the type of main histocompatibility antigen, and MHC for acquiring MHC three-dimensional structure information which is the three-dimensional structure of the main histocompatibility antigen determined by the main histocompatibility antigen determination means Based on the three-dimensional structure acquisition means, the MHC three-dimensional structure information acquired by the MHC three-dimensional structure acquisition means and the partial sequence of the target sequence acquired by the target sequence acquisition means, the major histocompatibility antigen and the A composite three-dimensional structure creating means for creating complex three-dimensional structure information with the partial sequence, and the composite three-dimensional structure creating means Structure evaluation index calculation means for calculating structure evaluation index value information, which is information related to an index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information using a quantum chemistry calculation method in the three-dimensional structure information And a structure evaluation index reference MHC binding partial sequence prediction means for predicting the MHC binding partial sequence from the partial sequences based on the structure evaluation index value information calculated by the structure evaluation index calculation means. It is characterized by that.

  This shows one example of the MHC binding partial sequence predicting means more specifically. According to this apparatus, the MHC binding partial sequence predicting means determines the type of the specific major histocompatibility antigen, acquires MHC conformation information that is the determined conformation of the major histocompatibility antigen, and obtains it. Based on the obtained MHC three-dimensional structure information and the obtained partial sequence of the target sequence, complex three-dimensional structure information of the major histocompatibility antigen and the partial sequence is created. The structure evaluation index value information, which is information related to the index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information, is calculated using a calculation method, and the partial array is calculated based on the calculated structure evaluation index value information. Since the MHC binding partial sequence is predicted from the inside, the structure evaluation index calculated using the quantum chemistry calculation method for the three-dimensional structure of the complex with MHC does not depend on the information of the known binding peptide. Based on the value, combined with a particular major histocompatibility antigen, it is possible to predict MHC binding subsequences that interact efficiently with high accuracy.

  The vaccine candidate partial sequence predicting device according to claim 11 is the vaccine candidate partial sequence predicting device according to any one of claims 1 to 10, wherein the non-self-recognizing partial sequence predicting means is a specific organism. Specific biological species sequence storage means for storing specific biological species sequence information that is information relating to the specific biological species amino acid sequence that is the amino acid sequence related to the species, and the specific biological species sequence information stored in the specific biological species sequence storage means On the other hand, non-self-recognition partial sequence search means for acquiring non-self-recognition search score information, which is a score at the time of search, by performing a search of the partial sequence of the target sequence created by the target sequence acquisition means The non-self-recognition from the partial sequences based on the non-self-recognition search score information acquired by the non-self-recognized partial sequence search means That further includes a search criteria non-self recognition moiety sequence estimating means for estimating an amount sequence characterized.

  This more specifically shows an example of the non-self-recognizing partial sequence predicting means. According to this apparatus, the non-self-recognizing partial sequence predicting means stores specific biological species sequence information that is information on a specific biological species amino acid sequence that is an amino acid sequence related to a specific biological species, and stores the stored specific biological species sequence information. In contrast, by performing a search of the partial sequence of the acquired target sequence, non-self-recognition search score information that is a score at the time of search is acquired, and based on the acquired non-self-recognition search score information, a partial Because non-self-recognizing partial sequences are predicted from the sequence, non-self-recognizing parts that are not recognized as self (have antigenicity) by evaluating whether they are recognized as self based on non-self-recognition search score information The sequence can be predicted efficiently and with high accuracy.

  The present invention also relates to a vaccine candidate partial sequence prediction method, and the vaccine candidate partial sequence prediction method according to claim 12 is information relating to a target sequence which is an amino acid sequence of a target protein or physiologically active polypeptide. A target sequence acquisition step for acquiring target sequence information; and the amino acid sequence that is not cleaved by a proteolytic enzyme or proteosome present in lysosome from the target sequence information acquired by the target sequence acquisition step, and the target sequence The amino acid capable of binding to a specific major histocompatibility antigen from the non-cleaved partial sequence prediction step for predicting a non-cut partial sequence that is a partial sequence of the target sequence and the target sequence information acquired by the target sequence acquisition step An MHC binding sequence, which is a partial sequence of the target sequence Non-self recognition that is an amino acid sequence that is not recognized as self from the target sequence information acquired by the MHC binding partial sequence prediction step for predicting a partial sequence and the target sequence acquisition step, and is a partial sequence of the target sequence From the non-self-recognizing partial sequence prediction step for predicting a partial sequence and the target sequence information acquired by the target sequence acquisition step, the amino acid sequence that is difficult to be mutated and is a partial sequence of the target sequence A non-mutated partial sequence prediction step for predicting a mutated partial sequence; the non-cut partial sequence predicted by the non-cut partial sequence prediction step; the MHC binding partial sequence predicted by the MHC binding partial sequence prediction step; The non-self-recognizing partial sequence predicted by the non-self-recognizing partial sequence prediction step; And / or a vaccine candidate partial sequence prediction step for predicting a vaccine candidate partial sequence that is the amino acid sequence effective as a vaccine based on the non-mutated partial sequence predicted by the non-mutant partial sequence prediction step. It is characterized by including.

  According to this method, target sequence information that is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide is obtained, and a proteolytic enzyme or proteosome present in the lysosome is obtained from the obtained target sequence information. An amino acid sequence that is not cleaved by the target sequence, is an amino acid sequence that can predict a non-cleaved partial sequence that is a partial sequence of the target sequence and can bind to a specific major histocompatibility antigen from the obtained target sequence information. Predicting an MHC binding partial sequence that is a partial sequence of the target sequence, and predicting a non-self-recognizing partial sequence that is a partial sequence of the target sequence that is an amino acid sequence that is not recognized as self from the acquired target sequence information, From the obtained target sequence information, it is an amino acid sequence that is difficult to mutate, and is a partial sequence of the target sequence. Based on the predicted non-mutated partial sequence, the predicted MHC binding partial sequence, the predicted non-self-recognizing partial sequence, and / or the predicted non-mutated partial sequence. Because the vaccine candidate partial sequence, which is an amino acid sequence effective as a vaccine, is predicted, from the target sequence information, 1) resistant to proteolytic enzymes or proteosomes present in lysosomes, 2) bound to MHC, and 3) self The vaccine candidate partial sequence optimal as a vaccine that satisfies the four conditions of being unrecognized as a peptide and 4) difficult to enter a mutation and capable of activating T cells can be predicted efficiently and with high accuracy.

  The vaccine candidate partial sequence prediction method according to claim 13 is the vaccine candidate partial sequence prediction method according to claim 12, wherein the non-cleavable partial sequence prediction step is a site cleaved by the proteolytic enzyme. Stored by the cleavage site-containing sequence storage step for storing the cleavage site-containing sequence information that is information on the cleavage site-containing sequence that is the amino acid sequence including several residues before and after the enzyme cleavage site, and the cleavage site-containing sequence storage step. A cleavage site-containing sequence amino acid appearance frequency calculating step for calculating cleavage site-containing sequence amino acid appearance frequency information, which is information relating to the appearance frequency of amino acids at positions corresponding to each amino acid residue in the cleavage site-containing sequence, and the cleavage site containing The cleavage site-containing sequence sequence calculated in the sequence amino acid appearance frequency calculation step Based on the non-acid appearance frequency information, based on the cleavage site-containing sequence score calculation step that calculates the cleavage site-containing sequence score calculation step that calculates the cleavage site-containing sequence score information, The cleavage site-containing sequence length partial sequence score for calculating the cleavage site-containing sequence length partial sequence score information corresponding to each partial sequence obtained by dividing the target sequence obtained by the objective sequence acquisition step into the length of the cleavage site-containing sequence A partial sequence cleaved at the enzyme cleavage site by determining the enzyme cleavage site based on the calculation step and the cleavage site-containing sequence length partial sequence score information calculated by the cleavage site-containing sequence length partial sequence score calculation step And a score-based non-cutting partial sequence predicting step for predicting as a non-cutting partial sequence.

  This shows one example of the non-cut partial sequence prediction step more specifically. According to this method, the non-cleavable partial sequence prediction step includes a cleavage site-containing sequence that is information on a cleavage site-containing sequence that is an amino acid sequence including several residues before and after the enzyme cleavage site, which is a site cleaved by a proteolytic enzyme. Information is stored, the cleavage site-containing sequence amino acid appearance frequency information, which is information about the appearance frequency of amino acids at positions corresponding to each amino acid residue in the stored cleavage site-containing sequence, is calculated, and the calculated cleavage site-containing sequence Each partial sequence obtained by calculating cleavage site-containing sequence score information based on amino acid appearance frequency information and dividing the obtained target sequence into the length of the cleavage site-containing sequence based on the calculated cleavage site-containing sequence score information The cleavage site-containing sequence length partial sequence score information corresponding to is calculated, and enzyme cleavage is performed based on the calculated cleavage site-containing sequence length partial sequence score information. Since the site is determined and the partial sequence cleaved at the enzyme cleavage site is predicted as a non-cleavable partial sequence, the enzyme cleavage site by the proteolytic enzyme or proteosome present in the lysosome based on the frequency analysis of the cleavage site-containing sequence It is possible to predict the non-cut partial sequence efficiently and with high accuracy.

  The vaccine candidate partial sequence prediction method according to claim 14 is the vaccine candidate partial sequence prediction method according to claim 12, wherein the non-cleavable partial sequence prediction step is a site cleaved by the proteolytic enzyme. From the cleavage site sequence storage step for storing the cleavage site sequence information, which is information relating to the cleavage site sequence that is the amino acid sequence of the enzyme cleavage site, and the cleavage site sequence information stored by the cleavage site sequence storage step, the known cleavage A cleavage site motif sequence extraction step for extracting a site motif sequence, and a motif for the target sequence acquired by the target sequence acquisition step using the cleavage site motif sequence extracted by the cleavage site motif sequence extraction step Enzymatic cleavage at the target sequence by performing a search The site of the target sequence is retrieved based on the cleavage site search score information acquired by the cleavage site motif search step obtained by the above-mentioned cleavage site motif search step. And a motif search reference non-cutting partial sequence prediction step of determining an enzyme cutting site and predicting a partial sequence cut at the enzyme cutting site as the non-cutting partial sequence.

  This shows one example of the non-cut partial sequence prediction step more specifically. According to this method, the non-cleavable partial sequence prediction step stores and stores the cleavage site sequence information, which is information related to the cleavage site sequence, which is the amino acid sequence of the enzyme cleavage site, which is a site cleaved by a proteolytic enzyme. Extracts a known cleavage site motif sequence from the cleavage site sequence information, searches the target sequence for the enzyme cleavage site using the extracted cleavage site motif sequence, and searches for the enzyme cleavage site in the target sequence. Obtain the cleavage site search score information that is the score at the time, determine the enzyme cleavage site of the target sequence based on the obtained cleavage site search score information, and the partial sequence cleaved at the enzyme cleavage site as a non-cleaved partial sequence Therefore, based on the motif search for the target sequence It is possible to predict the non-cutting portion arranged efficiently high precision by predicting the enzyme cleavage site with high precision by.

  The vaccine candidate partial sequence prediction method according to claim 15 is the vaccine candidate partial sequence prediction method according to any one of claims 12 to 14, wherein the MHC binding partial sequence prediction step includes the specific A major histocompatibility antigen determination step for determining the type of major histocompatibility antigen, and a number of residues before and after the MHC binding site that is a site to bind to the major histocompatibility antigen determined by the major histocompatibility antigen determination step. An MHC binding site-containing sequence storing step for storing MHC binding site-containing sequence information, which is information relating to the MHC binding site-containing sequence that is the amino acid sequence including the group, and the MHC binding site stored by the MHC binding site-containing sequence storage step Information on the appearance frequency of amino acids at positions corresponding to each amino acid residue in the site-containing sequence MHC binding site-containing sequence amino acid appearance frequency calculation step for calculating the MHC binding site-containing sequence amino acid appearance frequency information step, and the MHC binding site-containing sequence amino acid appearance frequency calculation step. Based on the MHC binding site-containing sequence score calculation step for calculating MHC binding site-containing sequence score information, and based on the MHC binding site-containing sequence score information calculated by the MHC binding site-containing sequence score calculation step, MHC binding site-containing sequence length portion for calculating MHC binding site-containing sequence length partial sequence score information corresponding to each partial sequence obtained by dividing the target sequence acquired in the target sequence acquisition step into the length of the MHC binding site-containing sequence A sequence score calculation step and the MHC binding site-containing sequence The MHC binding site is determined based on the MHC binding site-containing sequence length partial sequence score information calculated by the long partial sequence score calculation step, and the partial sequence including the MHC binding site is predicted as the MHC binding partial sequence The method further includes a step of predicting a score based MHC binding partial sequence.

  This shows one example of the MHC binding partial sequence prediction step more specifically. According to this method, the MHC binding subsequence prediction step determines the type of a specific major histocompatibility antigen, and determines several residues before and after the MHC binding site, which is the site that binds to the determined major histocompatibility antigen. Information on the frequency of appearance of amino acids at positions corresponding to each amino acid residue in the stored MHC binding site-containing sequence, storing MHC binding site-containing sequence information that is information on the MHC binding site-containing sequence that is an amino acid sequence including MHC binding site-containing sequence amino acid appearance frequency information is calculated, MHC binding site-containing sequence amino acid appearance frequency information is calculated based on the calculated MHC binding site-containing sequence amino acid appearance frequency information, and the calculated MHC binding site-containing sequence score is calculated Based on the information, the MHC corresponding to each partial sequence obtained by dividing the acquired target sequence into the length of the sequence containing the MHC binding site Combined site-containing sequence length partial sequence score information is calculated, an MHC binding site is determined based on the calculated MHC binding site-containing sequence length partial sequence score information, and the partial sequence including the MHC binding site is defined as an MHC binding partial sequence By predicting MHC binding sites that bind to specific major histocompatibility antigens with high accuracy based on amino acid frequency analysis of known MHC binding site-containing sequences corresponding to various major histocompatibility antigens , MHC binding partial sequences can be predicted efficiently and with high accuracy.

  The vaccine candidate partial sequence prediction method according to claim 16 is the vaccine candidate partial sequence prediction method according to any one of claims 12 to 14, wherein the MHC binding partial sequence prediction step includes the specific Major histocompatibility antigen determination step for determining the type of major histocompatibility antigen, and the amino acid sequence of the MHC binding site which is a site to bind to the major histocompatibility antigen determined by the major histocompatibility antigen determination step An MHC binding site sequence storing step for storing MHC binding site sequence information, which is information related to the MHC binding site sequence, and a known MHC binding site from the MHC binding site sequence information stored in the MHC binding site sequence storing step. MHC binding site motif sequence extracting step for extracting motif sequence, and MHC binding The MHC binding site in the target sequence is obtained by performing a motif search on the target sequence acquired in the target sequence acquisition step using the MHC binding site motif sequence extracted in the position motif sequence extraction step. MHC binding site motif search step for searching and acquiring MHC binding site search score information, which is a score at the time of search, and the MHC binding site based on the MHC binding site search score information acquired by the MHC binding site motif search step And a motif search reference MHC binding partial sequence prediction step of determining a site and predicting the partial sequence including the MHC binding site as the MHC binding partial sequence.

  This shows one example of the MHC binding partial sequence prediction step more specifically. According to this method, the MHC binding subsequence prediction step determines the type of a specific major histocompatibility antigen, and the MHC that is the amino acid sequence of the MHC binding site that is the site that binds to the determined major histocompatibility antigen. Stores MHC binding site sequence information, which is information related to the binding site sequence, extracts a known MHC binding site motif sequence from the stored MHC binding site sequence information, and obtains it using the extracted MHC binding site motif sequence A motif search is performed on the target sequence thus obtained to search for an MHC binding site in the target sequence, MHC binding site search score information that is a score at the time of search is obtained, and the acquired MHC binding site search score information is obtained. MHC binding site is determined based on this, and a partial sequence including the MHC binding site is predicted as an MHC binding partial sequence. A motif is detected by using a known MHC binding site sequence corresponding to the major histocompatibility antigen of the MHC, and an MHC binding site binding to a specific major histocompatibility antigen is predicted with high accuracy based on the motif search Thus, the MHC binding partial sequence can be predicted efficiently and with high accuracy.

  The vaccine candidate partial sequence prediction method according to claim 17 is the vaccine candidate partial sequence prediction method according to any one of claims 12 to 14, wherein the MHC binding partial sequence prediction step includes the specific A major histocompatibility antigen determination step for determining the type of major histocompatibility antigen, and a major histocompatibility antigen sequence that is the amino acid sequence of the major histocompatibility antigen determined by the major histocompatibility antigen determination step The main histocompatibility antigen determined by the main histocompatibility antigen determination step using the MHC sequence acquisition step for acquiring information of the main histocompatibility antigen sequence information and the target sequence acquired by the target sequence acquisition step. The MHC length partial sequence creation step for creating the MHC length partial sequence by dividing into lengths corresponding to the above types A complex three-dimensional structure that predicts complex three-dimensional structure information based on each MHC long partial sequence created by the MHC long partial sequence creating step and the major histocompatibility antigen sequence obtained by the MHC sequence obtaining step The amino acid interacting between the MHC long partial sequence and the major histocompatibility antigen sequence based on the structure three-dimensional structure information predicted by the structure prediction step and the complex three-dimensional structure prediction step Information on the affinity between the interacting amino acid determination step for determining interacting amino acid information, which is information on the set of amino acids, and the set of amino acids included in the interacting amino acid information determined by the interacting amino acid determination step Affinity that statistically calculates affinity information using 3D structure information of known proteins A calculation step, an affinity sum calculation step for calculating the sum of the affinity information among all the amino acid pairs calculated by the affinity calculation step, and the sum of the affinity information calculated by the affinity sum calculation step. An affinity reference MHC binding partial sequence prediction step for predicting the MHC binding partial sequence by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on To do.

  This shows one example of the MHC binding partial sequence prediction step more specifically. According to this method, the MHC binding subsequence prediction step determines the type of a specific major histocompatibility antigen and is information on the major histocompatibility antigen sequence that is the amino acid sequence of the determined major histocompatibility antigen. Obtain major histocompatibility antigen sequence information, divide the obtained target sequence into lengths corresponding to the determined major histocompatibility antigen types, create MHC length subsequences, and create each MHC Based on the long partial sequence and the obtained major histocompatibility antigen sequence, complex tertiary structure information is predicted, and based on the predicted complex tertiary structure information, the MHC long partial sequence and the major histocompatibility antigen sequence are Information on interaction amino acids, which is information on amino acid pairs interacting with each other, is determined, and information on affinity between the amino acid sets included in the determined interaction amino acid information is determined. Affinity information is statistically calculated using the three-dimensional structure information of known proteins, the sum of affinity information between all calculated amino acid pairs is calculated, and the sum of the calculated affinity information is calculated. Based on this, the MHC binding partial sequence is predicted by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen. Based on the affinity calculated statistically from the structure, an MHC binding partial sequence that binds to and interacts with a specific major histocompatibility antigen can be predicted with high speed and high accuracy.

  In addition, the vaccine candidate partial sequence prediction method according to claim 18 is the vaccine candidate partial sequence prediction method according to claim 17, wherein the MHC long partial sequence creation step includes the purpose acquired by the target sequence acquisition step. The method further comprises a slide splitting step in which the sequence is divided into the length corresponding to the type of the major histocompatibility antigen while sliding the amino acid residue from the beginning to create the MHC long partial sequence. And

  This more specifically shows an example of the MHC length partial sequence creation step. According to this method, the MHC length partial sequence creation step divides the acquired target sequence into lengths corresponding to the types of major histocompatibility antigens while sliding one amino acid residue at a time from the beginning. Since the partial sequence is created, an MHC length partial sequence that may be divided can be created without omission.

  The vaccine candidate partial sequence prediction method according to claim 19 is the vaccine candidate partial sequence prediction method according to claim 17 or 18, wherein the length corresponding to the type of the major histocompatibility antigen is 8 The number of residues is ˜18.

  This is a more specific example of the length corresponding to the type of major histocompatibility antigen. According to this method, since the length corresponding to the type of major histocompatibility antigen is 8 to 18 residues, for example, it is 8 to 12 residues for MHC class I, and MHC class II On the other hand, since the number of residues can be 12-18, an MHC length partial sequence having an optimum length corresponding to each MHC type can be prepared.

  Furthermore, the vaccine candidate partial sequence prediction method according to claim 20 is the vaccine candidate partial sequence prediction method according to any one of claims 17 to 19, wherein the MHC binding partial sequence prediction step includes the main tissue adaptation. MHC binding, which is information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen determined by the sex antigen determination step and each amino acid residue of the major histocompatibility antigen sequence The method further includes a MHC-binding amino acid residue distance value storing step for storing amino acid residue distance value information, wherein the affinity calculation step stores the affinity information by the MHC-binding amino acid residue distance value storing step. Distance value information between the MHC-binding amino acid residues and / or the three-dimensional structure information of the known protein And further comprising a distance value based affinity calculation step of calculating using available statistical potentials.

  This more specifically shows an example of the MHC binding partial sequence prediction step and the affinity calculation step. According to this method, the MHC binding subsequence prediction step includes a distance value between each amino acid residue of the amino acid sequence that binds to the determined major histocompatibility antigen and each amino acid residue of the major histocompatibility antigen sequence. MHC binding amino acid residue distance value information, which is information relating to the information, and the affinity calculation step includes the affinity information, the stored MHC binding amino acid residue distance value information, and / or the three-dimensional structure information of the known protein. Since it is calculated using the statistical potential using, it does not depend on the information of the known binding peptide, and it is calculated using the statistical potential using the distance between MHC-binding amino acid residues from the 3D complex structure with MHC. Based on the determined affinity, the MHC binding partial sequence that binds to and interacts with a specific major histocompatibility antigen is predicted with high speed and high accuracy. It can be.

  The vaccine candidate partial sequence prediction method according to claim 21 is the vaccine candidate partial sequence prediction method according to any one of claims 12 to 14, wherein the MHC binding partial sequence prediction step includes the specific A main histocompatibility antigen determining step for determining the type of main histocompatibility antigen, and an MHC for acquiring MHC three-dimensional structure information that is a three-dimensional structure of the main histocompatibility antigen determined by the main histocompatibility antigen determination step Based on the three-dimensional structure acquisition step, the MHC three-dimensional structure information acquired by the MHC three-dimensional structure acquisition step and the partial sequence of the target sequence acquired by the target sequence acquisition step, the major histocompatibility antigen and the A composite three-dimensional structure creating step for creating complex three-dimensional structure information with the partial sequence; In the complex three-dimensional structure information created by the creation step, structure evaluation index value information, which is information related to an index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information using a quantum chemical calculation method, A structure evaluation index reference MHC binding portion that predicts the MHC binding partial sequence from the partial sequences based on the structure evaluation index calculation step to be calculated and the structure evaluation index value information calculated by the structure evaluation index calculation step A sequence predicting step.

  This shows one example of the MHC binding partial sequence prediction step more specifically. According to this method, the MHC binding partial sequence prediction step determines the type of the specific major histocompatibility antigen, obtains MHC conformation information that is the determined conformation of the major histocompatibility antigen, and obtains it. Based on the obtained MHC three-dimensional structure information and the acquired partial sequence of the target sequence, a complex three-dimensional structure information of the major histocompatibility antigen and the partial sequence is created. The structure evaluation index value information, which is information related to the index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information, is calculated using a calculation method, and based on the calculated structure evaluation index value information, Since the MHC binding partial sequence is predicted from the inside, it is not dependent on the information of known binding peptides, and the structure evaluation calculated using the quantum chemistry calculation method for the three-dimensional structure of the complex with MHC Based on the index value, combined with a particular major histocompatibility antigen, it is possible to predict MHC binding subsequences that interact efficiently with high accuracy.

  Furthermore, the vaccine candidate partial sequence prediction method according to claim 22 is the vaccine candidate partial sequence prediction method according to any one of claims 12 to 21, wherein the non-self-recognizing partial sequence prediction step includes a specific organism. A specific species sequence storage step for storing specific species sequence information, which is information relating to a specific species amino acid sequence, which is the amino acid sequence for the species, and the specific species sequence information stored by the specific species sequence storage step. On the other hand, a non-self-recognition partial sequence search step of acquiring non-self-recognition search score information that is a score at the time of searching by executing a search of the partial sequence of the target sequence created by the target sequence acquisition step; , Based on the non-self-recognition search score information acquired by the non-self-recognition partial sequence search step, the part Wherein the out of the column further comprises a search criteria non-self recognition moiety sequence prediction step of predicting the non-self recognition moiety sequence.

  This more specifically shows an example of the non-self-recognizing partial sequence prediction step. According to this method, the non-self-recognizing partial sequence prediction step stores the specific species sequence information that is information on the specific species amino acid sequence that is an amino acid sequence related to the specific species, and stores the stored specific species sequence information. In contrast, by performing a search of the partial sequence of the acquired target sequence, non-self-recognition search score information that is a score at the time of search is acquired, and based on the acquired non-self-recognition search score information, a partial Because non-self-recognizing partial sequences are predicted from the sequence, non-self-recognizing parts that are not recognized as self (have antigenicity) by evaluating whether they are recognized as self based on non-self-recognizing search score information The sequence can be predicted efficiently and with high accuracy.

  In addition, the present invention relates to a program, and the program for causing a computer to execute the vaccine candidate partial sequence prediction method according to claim 23 is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide. A target sequence obtaining step for obtaining certain target sequence information, and the amino acid sequence that is not cleaved by a proteolytic enzyme or proteosome present in lysosome from the target sequence information obtained by the target sequence obtaining step, A non-cleaved partial sequence prediction step for predicting a non-cut partial sequence that is a partial sequence of the sequence, and the target sequence information acquired by the target sequence acquisition step, and the above-described target sequence-binding information can bind to a specific major histocompatibility antigen. Amino acid sequence, part of the target sequence An MHC binding partial sequence prediction step that predicts an MHC binding partial sequence that is a sequence, and the amino acid sequence that is not recognized as self from the target sequence information acquired by the target sequence acquisition step, the partial sequence of the target sequence A non-self-recognition partial sequence prediction step for predicting a non-self-recognition partial sequence, and the target sequence information obtained by the target sequence acquisition step, the amino acid sequence that is difficult to be mutated, A non-mutated partial sequence predicting step for predicting a non-mutated partial sequence which is a partial sequence, the non-cut partial sequence predicted by the non-cut partial sequence predicting step, and the above-mentioned predicted by the MHC binding partial sequence predicting step MHC binding partial sequence, the non-predicted by the non-self-recognizing partial sequence prediction step A vaccine candidate part that predicts a vaccine candidate partial sequence that is the amino acid sequence effective as a vaccine based on the self-recognizing partial sequence and / or the non-mutated partial sequence predicted by the non-mutated partial sequence prediction step A sequence prediction step.

  According to this program, target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide, is obtained, and a proteolytic enzyme or proteosome present in the lysosome is obtained from the obtained target sequence information. An amino acid sequence that is not cleaved by the target sequence, is an amino acid sequence that can predict a non-cleaved partial sequence that is a partial sequence of the target sequence and can bind to a specific major histocompatibility antigen from the obtained target sequence information. Predicting an MHC binding partial sequence that is a partial sequence of the target sequence, and predicting a non-self-recognizing partial sequence that is a partial sequence of the target sequence that is an amino acid sequence that is not recognized as self from the acquired target sequence information, Based on the obtained target sequence information, it is an amino acid sequence that is difficult to mutate, and is a part of the target sequence. Predicted non-mutated subsequences that are sequences, predicted non-cleaved subsequences, predicted MHC binding subsequences, predicted nonself-recognizing subsequences, and / or predicted nonmutated subsequences Based on this, a candidate vaccine partial sequence that is an amino acid sequence effective as a vaccine is predicted. Therefore, from the target sequence information, 1) it has resistance to proteolytic enzymes or proteosomes present in lysosomes, 2) binds to MHC, 3 It is possible to efficiently and accurately predict a vaccine candidate partial sequence that is optimal as a vaccine that satisfies the four conditions of being not recognized as a self-peptide, and 4) difficult to introduce mutations, and that can activate T cells. .

  The program according to claim 24 is the program according to claim 23, wherein the non-cleavable partial sequence prediction step includes several residues before and after the enzyme cleavage site, which is a site cleaved by the proteolytic enzyme. A cleavage site-containing sequence storage step for storing cleavage site-containing sequence information, which is information on the cleavage site-containing sequence that is the amino acid sequence, and each amino acid residue in the cleavage site-containing sequence stored by the cleavage site-containing sequence storage step. Calculated by the cleavage site-containing sequence amino acid appearance frequency calculating step for calculating the cleavage site-containing sequence amino acid appearance frequency information, which is information on the appearance frequency of the amino acid at the position corresponding to the group, and the cleavage site-containing sequence amino acid appearance frequency calculating step. Based on the cleavage site-containing sequence amino acid appearance frequency information, The cleavage site-containing sequence score calculation step for calculating the contained sequence score information, and the objective obtained by the objective sequence acquisition step based on the cleavage site-containing sequence score information calculated by the cleavage site-containing sequence score calculation step A cleavage site-containing sequence length partial sequence score calculation step for calculating a cleavage site-containing sequence length partial sequence score information corresponding to each partial sequence obtained by dividing the sequence into the lengths of the cleavage site-containing sequences, and the cleavage site-containing sequence length portion. Scoring criteria for determining the enzyme cleavage site based on the cleavage site-containing sequence length partial sequence score information calculated in the sequence score calculation step and predicting the partial sequence cleaved at the enzyme cleavage site as the non-cleavable partial sequence An uncut partial sequence predicting step.

  This shows one example of the non-cut partial sequence prediction step more specifically. According to this program, the non-cleavable partial sequence prediction step is a cleavage site-containing sequence that is information on a cleavage site-containing sequence that is an amino acid sequence including several residues before and after the enzyme cleavage site, which is a site cleaved by a proteolytic enzyme. Information is stored, the cleavage site-containing sequence amino acid appearance frequency information, which is information about the appearance frequency of amino acids at positions corresponding to each amino acid residue in the stored cleavage site-containing sequence, is calculated, and the calculated cleavage site-containing sequence Each partial sequence obtained by calculating cleavage site-containing sequence score information based on amino acid appearance frequency information and dividing the obtained target sequence into the length of the cleavage site-containing sequence based on the calculated cleavage site-containing sequence score information The cleavage site-containing sequence length partial sequence score information corresponding to is calculated, based on the calculated cleavage site-containing sequence length partial sequence score information Since a partial cleavage site is determined and a partial sequence cleaved at the enzyme cleavage site is predicted as a non-cleaved partial sequence, an enzyme by a proteolytic enzyme or proteosome existing in the lysosome based on frequency analysis of the cleavage site-containing sequence By predicting a cleavage site with high accuracy, an uncut partial sequence can be efficiently and accurately predicted.

  The program according to claim 25 is the program according to claim 23, wherein the non-cleavable partial sequence prediction step is a cleavage that is the amino acid sequence of an enzyme cleavage site that is a site cleaved by the proteolytic enzyme. A cutting site sequence storing step for storing cutting site sequence information, which is information related to the site sequence, and a cutting site motif sequence for extracting a known cutting site motif sequence from the cutting site sequence information stored in the cutting site sequence storing step In the target sequence by performing a motif search on the target sequence acquired by the target sequence acquisition step using the extraction step and the cleavage site motif sequence extracted by the cleavage site motif sequence extraction step Search for the above enzyme cleavage site A cleavage site motif search step for acquiring site search score information; and the enzyme cleavage site of the target sequence is determined based on the cleavage site search score information acquired by the cleavage site motif search step, and the enzyme cleavage site And a motif search reference non-cutting partial sequence prediction step of predicting the cut partial sequence as the non-cutting partial sequence.

  This shows one example of the non-cut partial sequence prediction step more specifically. According to this program, the non-cleavable partial sequence prediction step stores and stores the cleavage site sequence information, which is information about the cleavage site sequence, which is the amino acid sequence of the enzyme cleavage site, which is the site cleaved by the proteolytic enzyme. Extracts a known cleavage site motif sequence from the cleavage site sequence information, searches the target sequence for the enzyme cleavage site using the extracted cleavage site motif sequence, and searches for the enzyme cleavage site in the target sequence. Obtain the cleavage site search score information that is the score at the time, determine the enzyme cleavage site of the target sequence based on the obtained cleavage site search score information, and the partial sequence cleaved at the enzyme cleavage site as a non-cleaved partial sequence Based on the motif search for the target sequence, the proteolytic enzyme or protein present in the lysosome Uncut partial sequences can be predicted efficiently high precision by predicting the enzyme cleavage site by endosomal with high accuracy.

  The program according to claim 26 is the program according to any one of claims 23 to 25, wherein the MHC binding partial sequence prediction step determines the type of the specific major histocompatibility antigen. Major histocompatibility antigen determination step, and MHC binding, which is the amino acid sequence including several residues before and after the MHC binding site, which is the site that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determination step An MHC binding site-containing sequence storage step for storing MHC binding site-containing sequence information, which is information relating to the site-containing sequence, and each amino acid residue in the MHC binding site-containing sequence stored by the MHC binding site-containing sequence storage step. MHC binding site-containing sequence amino acid output that is information on the frequency of occurrence of amino acids at the corresponding position MHC binding site-containing sequence amino acid appearance frequency calculating step for calculating frequency information, and MHC binding site-containing sequence amino acid appearance frequency calculating step calculated based on the MHC binding site-containing sequence amino acid appearance frequency calculating step Obtained by the target sequence acquisition step based on the MHC binding site-containing sequence score calculation step calculated from the MHC binding site-containing sequence score calculation step and the MHC binding site-containing sequence score calculation step. An MHC binding site-containing sequence length partial sequence score calculation step for calculating MHC binding site-containing sequence length partial sequence score information corresponding to each partial sequence obtained by dividing the target sequence into the length of the MHC binding site-containing sequence; Binding site-containing sequence length Calculated by partial sequence score calculation step The MHC binding site-containing sequence length partial sequence scoring information is used to determine the MHC binding site and to predict the partial sequence including the MHC binding site as the MHC binding partial sequence. And further including.

  This shows one example of the MHC binding partial sequence prediction step more specifically. According to this program, the MHC binding subsequence prediction step determines the type of a specific major histocompatibility antigen, and determines several residues before and after the MHC binding site, which is the site that binds to the determined major histocompatibility antigen. Information on the frequency of appearance of amino acids at positions corresponding to each amino acid residue in the stored MHC binding site-containing sequence, storing MHC binding site-containing sequence information that is information on the MHC binding site-containing sequence that is an amino acid sequence including MHC binding site-containing sequence amino acid appearance frequency information is calculated, MHC binding site-containing sequence amino acid appearance frequency information is calculated based on the calculated MHC binding site-containing sequence amino acid appearance frequency information, and the calculated MHC binding site-containing sequence score is calculated Corresponding to each partial sequence obtained by dividing the obtained target sequence into the length of the MHC binding site-containing sequence based on the information HC binding site-containing sequence length partial sequence score information is calculated, an MHC binding site-containing sequence length partial sequence score information is determined, an MHC binding site is determined, and the partial sequence including the MHC binding site is determined as an MHC binding partial sequence Therefore, based on amino acid frequency analysis of known MHC binding site-containing sequences corresponding to various major histocompatibility antigens, MHC binding sites that bind to specific major histocompatibility antigens can be predicted with high accuracy. Thus, the MHC binding partial sequence can be predicted efficiently and with high accuracy.

  The program according to claim 27 is the program according to any one of claims 23 to 25, wherein the MHC binding partial sequence prediction step determines the type of the specific major histocompatibility antigen. Information relating to the major histocompatibility antigen determination step and the MHC binding site sequence that is the amino acid sequence of the MHC binding site that is the site that binds to the major histocompatibility antigen determined in the major histocompatibility antigen determination step An MHC binding site sequence storing step for storing MHC binding site sequence information, and an MHC binding site motif sequence for extracting a known MHC binding site motif sequence from the MHC binding site sequence information stored in the MHC binding site sequence storing step Extraction by the extraction step and the MHC binding site motif sequence extraction step The MHC binding site in the target sequence is searched by performing a motif search on the target sequence obtained in the target sequence acquisition step using the MHC binding site motif sequence thus obtained, and the score at the time of the search An MHC binding site motif search step for acquiring the MHC binding site search score information, and the MHC binding site search score information acquired by the MHC binding site motif search step to determine the MHC binding site, And a motif search reference MHC binding partial sequence prediction step for predicting the partial sequence including the binding site as the MHC binding partial sequence.

  This shows one example of the MHC binding partial sequence prediction step more specifically. According to this program, the MHC binding subsequence prediction step determines the type of a specific major histocompatibility antigen, and the MHC that is the amino acid sequence of the MHC binding site that is the site that binds to the determined major histocompatibility antigen. Stores MHC binding site sequence information, which is information related to the binding site sequence, extracts a known MHC binding site motif sequence from the stored MHC binding site sequence information, and obtains it using the extracted MHC binding site motif sequence A motif search is performed on the target sequence thus obtained to search for an MHC binding site in the target sequence, MHC binding site search score information that is a score at the time of search is obtained, and the acquired MHC binding site search score information is obtained. MHC binding site is determined based on this, and a partial sequence including the MHC binding site is predicted as an MHC binding partial sequence. Detecting motifs using known MHC binding site sequences corresponding to various major histocompatibility antigens, and, based on the motif search, highly accurate MHC binding sites that bind to specific major histocompatibility antigens By predicting, an MHC binding partial sequence can be predicted efficiently and with high accuracy.

  The program according to claim 28 is the program according to any one of claims 23 to 25, wherein the MHC binding partial sequence prediction step determines the type of the specific major histocompatibility antigen. Major histocompatibility antigen sequence information, which is information on a major histocompatibility antigen sequence that is the amino acid sequence of the major histocompatibility antigen determined by the major histocompatibility antigen determination step And dividing the target sequence acquired by the target sequence acquisition step into lengths corresponding to the types of the major histocompatibility antigens determined by the major histocompatibility antigen determination step. Then, an MHC length partial sequence creating step for creating an MHC length partial sequence, and the above MHC length partial sequence creating step A complex three-dimensional structure prediction step for predicting complex three-dimensional structure information based on each MHC long partial sequence prepared by the above and the major histocompatibility antigen sequence acquired by the MHC sequence acquisition step; An interacting amino acid that is information on the set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence based on the complex three-dimensional structure information predicted by the structure prediction step Affinity information, which is information on the affinity between the amino acid set included in the interaction amino acid determination step determined by the interaction amino acid determination step and the interaction amino acid determination step determined by the interaction amino acid determination step, Affinity calculation step statistically calculated using structural information, and the affinity calculation step Based on the affinity sum calculation step for calculating the sum of the affinity information among all the amino acid pairs calculated by the step, and the MHC length based on the sum of the affinity information calculated by the affinity sum calculation step. The method further comprises an affinity reference MHC binding partial sequence prediction step for predicting the MHC binding partial sequence by evaluating the affinity between the partial sequence and the major histocompatibility antigen.

  This shows one example of the MHC binding partial sequence prediction step more specifically. According to this program, the MHC binding subsequence prediction step determines the type of a specific major histocompatibility antigen and is information on the major histocompatibility antigen sequence that is the amino acid sequence of the determined major histocompatibility antigen. The major histocompatibility antigen sequence information is obtained, the obtained target sequence is divided into lengths corresponding to the determined major histocompatibility antigen types, MHC length subsequences are created, and each created MHC Based on the long partial sequence and the obtained major histocompatibility antigen sequence, complex tertiary structure information is predicted, and based on the predicted complex tertiary structure information, the MHC long partial sequence and the major histocompatibility antigen sequence are The interaction amino acid information, which is information on the set of amino acids interacting with each other, is determined, and the affinity between the amino acid sets included in the determined interaction amino acid information is determined. Affinity information, which is information to be calculated, is statistically calculated using the three-dimensional structure information of known proteins, the sum of the affinity information between all the calculated amino acid pairs is calculated, and the calculated affinity information Since the MHC binding partial sequence is predicted by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on the sum, it is not dependent on the information of the known binding peptide, and the complex with MHC Based on the affinity calculated statistically from the three-dimensional structure of the body, an MHC binding partial sequence that binds to and interacts with a specific major histocompatibility antigen can be predicted with high speed and high accuracy.

  Further, the program according to claim 29 is the program according to claim 28, wherein the MHC length partial sequence creation step is configured such that the target sequence acquired by the target sequence acquisition step is changed by one amino acid residue from the beginning. The method further comprises a slide dividing step of generating the MHC long partial sequence by sliding into the length corresponding to the type of the major histocompatibility antigen while sliding.

  This more specifically shows an example of the MHC length partial sequence creation step. According to this program, the MHC length partial sequence creation step divides the acquired target sequence into lengths corresponding to the types of major histocompatibility antigens while sliding one amino acid residue from the beginning, Since the partial sequence is created, an MHC length partial sequence that may be divided can be created without omission.

  The program according to claim 30 is the program according to claim 28 or 29, wherein the length corresponding to the type of the major histocompatibility antigen is 8 to 18 residues. And

  This is a more specific example of the length corresponding to the type of major histocompatibility antigen. According to this program, the length corresponding to the major histocompatibility antigen type is 8 to 18 residues, so for example, it is 8 to 12 residues for MHC class I and MHC class II. On the other hand, since the number of residues can be 12 to 18, it is possible to create an MHC length partial sequence having an optimum length corresponding to each MHC type.

  Further, the program according to claim 31 is the program according to any one of claims 28 to 30, wherein the MHC binding partial sequence prediction step is performed by the main histocompatibility antigen determination step. Stores distance value information between MHC-binding amino acid residues, which is information on the distance value between each amino acid residue of the amino acid sequence that binds to the histocompatibility antigen and each amino acid residue of the main histocompatibility antigen sequence. The method further includes a step of storing a distance value between MHC-binding amino acid residues, wherein the affinity calculating step stores the affinity information as the distance value information between MHC-binding amino acid residues stored in the MHC-binding amino acid residue distance value storing step. And / or calculation using the statistical potential using the three-dimensional structure information of the known protein. Characterized in that it further comprises a distance value based affinity calculation step of.

  This more specifically shows an example of the MHC binding partial sequence prediction step and the affinity calculation step. According to this program, the MHC binding subsequence prediction step includes a distance value between each amino acid residue of the amino acid sequence that binds to the determined major histocompatibility antigen and each amino acid residue of the major histocompatibility antigen sequence. MHC binding amino acid residue distance value information, which is information relating to the information, and the affinity calculation step includes the affinity information, the stored MHC binding amino acid residue distance value information, and / or the three-dimensional structure information of the known protein. Since it is calculated using the statistical potential using, it does not depend on the information of the known binding peptide, and it is calculated using the statistical potential using the distance between MHC-binding amino acid residues from the 3D complex structure with MHC. Based on the determined affinity, fast and accurate prediction of MHC binding subsequences that bind to and interact with specific major histocompatibility antigens It is possible.

  The program according to claim 32 is the program according to any one of claims 23 to 25, wherein the MHC binding partial sequence prediction step determines the type of the specific major histocompatibility antigen. A main histocompatibility antigen determination step, an MHC three-dimensional structure acquisition step for acquiring MHC three-dimensional structure information which is a three-dimensional structure of the main histocompatibility antigen determined by the main histocompatibility antigen determination step, and the MHC three-dimensional structure Based on the MHC three-dimensional structure information acquired in the acquisition step and the partial sequence of the target sequence acquired in the target sequence acquisition step, the complex three-dimensional structure information of the major histocompatibility antigen and the partial sequence is obtained. The composite 3D structure creation step to be created and the composite 3D structure created step In structure three-dimensional structure information, a structure evaluation index calculating step for calculating structure evaluation index value information, which is information related to an index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information using a quantum chemistry calculation method; And a structure evaluation index reference MHC binding partial sequence prediction step for predicting the MHC binding partial sequence from the partial sequences based on the structure evaluation index value information calculated by the structure evaluation index calculation step. It is characterized by.

  This shows one example of the MHC binding partial sequence prediction step more specifically. According to this program, the MHC binding partial sequence prediction step determines the type of the specific major histocompatibility antigen, obtains MHC conformation information that is the determined conformation of the major histocompatibility antigen, and obtains it. Based on the obtained MHC three-dimensional structure information and the acquired partial sequence of the target sequence, a complex three-dimensional structure information of the major histocompatibility antigen and the partial sequence is created. The structure evaluation index value information, which is information related to the index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information, is calculated using a calculation method, and the partial array is calculated based on the calculated structure evaluation index value information. Since the MHC binding partial sequence is predicted from the inside, it was calculated using the quantum chemistry calculation method for the three-dimensional structure of the complex with MHC without depending on the information of known binding peptides Based on the concrete evaluation index value, combined with a particular major histocompatibility antigen, it is possible to predict MHC binding subsequences that interact efficiently with high accuracy.

  Further, the program according to claim 33 is the program according to any one of claims 23 to 32, wherein the non-self-recognizing partial sequence prediction step is a specific biological species that is the amino acid sequence related to a specific biological species. Created by the target sequence acquisition step for the specific species sequence storage step for storing the specific species sequence information, which is information relating to the amino acid sequence, and the specific species sequence information stored by the specific species sequence storage step. A non-self-recognition partial sequence search step for obtaining non-self-recognition search score information, which is a score at the time of search, by executing a search of the partial sequence of the target sequence, and the non-self-recognition partial sequence search step Based on the acquired non-self-recognition search score information, the non-self-recognized partial sequence is selected from the partial sequences. Characterized in that it further comprises a search criteria non-self recognition moiety sequence prediction step of measuring.

  This more specifically shows an example of the non-self-recognizing partial sequence prediction step. According to this program, the non-self-recognizing partial sequence prediction step stores the specific species sequence information that is information on the specific species amino acid sequence that is the amino acid sequence related to the specific species, and the stored specific species sequence information. In contrast, by performing a search of the partial sequence of the acquired target sequence, non-self-recognition search score information that is a score at the time of search is acquired, and based on the acquired non-self-recognition search score information, a partial Because non-self-recognizing partial sequences are predicted from the sequence, non-self-recognizing parts that are not recognized as self (have antigenicity) by evaluating whether they are recognized as self based on non-self-recognizing search score information The sequence can be predicted efficiently and with high accuracy.

  Further, the present invention relates to a recording medium, and the computer-readable recording medium according to claim 34 records the program according to any one of claims 23 to 33. .

  According to this recording medium, the program described in any one of claims 23 to 33 is realized using a computer by causing the computer to read and execute the program recorded on the recording medium. The same effect as each of these programs can be obtained.

  In addition, the present invention relates to an MHC binding partial sequence prediction apparatus, and the MHC binding partial sequence prediction apparatus according to claim 35 is information relating to a target sequence which is an amino acid sequence of a target protein or physiologically active polypeptide. Target sequence acquisition means for acquiring target sequence information, major histocompatibility antigen determination means for determining the type of a specific major histocompatibility antigen, and the major histocompatibility determined by the major histocompatibility antigen determination means MHC sequence acquisition means for acquiring main histocompatibility antigen sequence information, which is information on the main histocompatibility antigen sequence that is the amino acid sequence of the antigen, and the target sequence acquired by the target sequence acquisition means The MHC length portion is divided into lengths corresponding to the types of the major histocompatibility antigens determined by the sex antigen determination means. MHC length partial sequence creating means for creating a sequence, each MHC length partial sequence created by the MHC length partial sequence creating means, and the major histocompatibility antigen sequence obtained by the MHC sequence obtaining means Complex three-dimensional structure prediction means for predicting body three-dimensional structure information, and based on the complex three-dimensional structure information predicted by the complex three-dimensional structure prediction means, the MHC long partial sequence and the major histocompatibility antigen sequence Interacting amino acid determining means for determining interacting amino acid information, which is information relating to the set of amino acids interacting with each other, and the amino acids included in the interacting amino acid information determined by the interacting amino acid determining means Affinity information, which is information on the affinity between pairs, is statistically calculated using known protein conformation information. An affinity calculation means for calculating, an affinity sum calculation means for calculating the sum of the affinity information among all the amino acid pairs calculated by the affinity calculation means, and the affinity information calculated by the affinity sum calculation means MHC, which is the amino acid sequence capable of binding to the specific major histocompatibility antigen by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on the sum of An affinity reference MHC binding partial sequence predicting means for predicting the binding partial sequence is provided.

  According to this apparatus, target sequence information, which is information relating to a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide, is obtained, a type of a specific main histocompatibility antigen is determined, and the determined main tissue Acquire major histocompatibility antigen sequence information, which is information on major histocompatibility antigen sequences that are amino acid sequences of compatible antigens, and obtain the target sequence length corresponding to the determined major histocompatibility antigen type To generate MHC long partial sequences, and based on each of the generated MHC long partial sequences and the obtained major histocompatibility antigen sequence, complex three-dimensional structure information is predicted, and predicted complex three-dimensional Based on the structural information, the interacting amino acid information, which is information on the set of amino acids interacting between the MHC long subsequence and the major histocompatibility antigen sequence, is determined. Affinity information, which is information related to the affinity between amino acid sets included in the determined interaction amino acid information, is statistically calculated using the three-dimensional structure information of known proteins, and all calculated amino acid sets Between the specific major histocompatibility antigen and the major histocompatibility antigen by evaluating the affinity between the MHC long subsequence and the major histocompatibility antigen based on the calculated sum of the affinity information. Since the MHC binding partial sequence, which is an amino acid sequence that can be bound, is predicted, based on the affinity calculated statistically from the three-dimensional structure of the complex with MHC without depending on the information of known binding peptides, MHC binding subsequences that bind to and interact with specific major histocompatibility antigens can be predicted with high speed and high accuracy.

  Further, the MHC binding partial sequence prediction apparatus according to claim 36 is the MHC binding partial sequence prediction apparatus according to claim 35, wherein the MHC long partial sequence creation means is the purpose acquired by the target sequence acquisition means. A slide splitting means for creating the MHC long partial sequence by splitting the sequence into the length corresponding to the type of the major histocompatibility antigen while sliding the amino acid residue from the top one by one; Features.

  This more specifically shows one example of the MHC length partial sequence creating means. According to this apparatus, the MHC length partial sequence creating means divides the acquired target sequence into lengths corresponding to the types of major histocompatibility antigens while sliding the amino acid residues one by one from the beginning. Since the partial sequence is created, an MHC length partial sequence that may be divided can be created without omission.

  The MHC binding partial sequence prediction apparatus according to claim 37 is the MHC binding partial sequence prediction apparatus according to claim 35 or 36, wherein the length corresponding to the type of the major histocompatibility antigen is 8 The number of residues is ˜18.

  This is a more specific example of the length corresponding to the type of major histocompatibility antigen. According to this apparatus, since the length corresponding to the type of major histocompatibility antigen is 8 to 18 residues, for example, it is 8 to 12 residues for MHC class I, and MHC class II On the other hand, since the number of residues can be 12-18, an MHC length partial sequence having an optimum length corresponding to each MHC type can be prepared.

  The MHC binding partial sequence prediction apparatus according to claim 38 is the MHC binding partial sequence prediction apparatus according to any one of claims 35 to 37, wherein the MHC binding partial sequence prediction apparatus is determined by the major histocompatibility antigen determination means. Stores MHC-binding amino acid residue distance value information, which is information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen and each amino acid residue of the major histocompatibility antigen sequence. MHC-binding amino acid residue distance value storage means, wherein the affinity calculation means stores the affinity information between the MHC-binding amino acid residue distance value storage means stored in the MHC-binding amino acid residue distance value storage means. Distance value based affinity calculated using statistical potential using information and / or the 3D structure information of the known protein And further comprising a detection means.

  This more specifically shows an example of the affinity calculation means. According to this apparatus, the MHC binding amino acid residue, which is information on the distance value between each amino acid residue of the amino acid sequence that binds to the determined major histocompatibility antigen and each amino acid residue of the major histocompatibility antigen sequence, is obtained. The group distance value information is stored, and the affinity calculation means uses the statistical potential using the stored MHC binding amino acid residue distance value information and / or the known three-dimensional structure information of the protein. Because it is calculated, it does not depend on the information of known binding peptides, and it is specified based on the affinity calculated using the statistical potential using the distance between MHC-binding amino acid residues from the 3D complex structure with MHC. MHC binding subsequences that bind to and interact with major histocompatibility antigens can be predicted with high speed and high accuracy.

  The present invention also relates to a method for predicting an MHC binding partial sequence, and the method for predicting an MHC binding partial sequence according to claim 39 is information relating to a target sequence which is an amino acid sequence of the target protein or physiologically active polypeptide. A target sequence acquisition step for acquiring target sequence information, a main histocompatibility antigen determination step for determining the type of a specific main histocompatibility antigen, and the main histocompatibility determined by the main histocompatibility antigen determination step An MHC sequence acquisition step for acquiring main histocompatibility antigen sequence information, which is information on the main histocompatibility antigen sequence that is the amino acid sequence of the antigen, and the target sequence acquired by the target sequence acquisition step is the main tissue compatibility Length corresponding to the type of major histocompatibility antigen determined by the sex antigen determination step MHC length partial sequence creation step for dividing and creating an MHC length partial sequence, each MHC length partial sequence created by the MHC length partial sequence creation step, and the main tissue compatibility obtained by the MHC sequence acquisition step A complex three-dimensional structure prediction step for predicting complex three-dimensional structure information based on an antigen sequence, and the MHC long partial sequence and the above-described one based on the complex three-dimensional structure information predicted by the complex three-dimensional structure prediction step An interacting amino acid determining step for determining interacting amino acid information, which is information relating to the set of amino acids interacting with a major histocompatibility antigen sequence, and the interaction determined by the interacting amino acid determining step Affinity information, which is information related to the affinity between the above amino acid pairs included in the amino acid information Affinity calculation step for calculating the total of the affinity information among all the amino acid pairs calculated by the affinity calculation step and statistically calculating the three-dimensional structure information of the known protein and the affinity calculation step And evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen on the basis of the sum of the affinity information calculated in the step of calculating the affinity sum, the specific major tissue An affinity reference MHC binding partial sequence prediction step for predicting an MHC binding partial sequence that is the amino acid sequence capable of binding to a compatible antigen.

  According to this method, target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide, is obtained, a type of a specific major histocompatibility antigen is determined, and the determined main tissue Acquire major histocompatibility antigen sequence information, which is information on major histocompatibility antigen sequences that are amino acid sequences of compatible antigens, and obtain the target sequence length corresponding to the determined major histocompatibility antigen type To generate MHC long partial sequences, and based on each of the generated MHC long partial sequences and the obtained major histocompatibility antigen sequence, complex three-dimensional structure information is predicted, and predicted complex three-dimensional Based on the structural information, the interacting amino acid information, which is information on the set of amino acids interacting between the MHC long subsequence and the major histocompatibility antigen sequence, is determined. Affinity information, which is information related to the affinity between amino acid sets included in the determined interaction amino acid information, is statistically calculated using the three-dimensional structure information of known proteins, and all calculated amino acid sets Between the specific major histocompatibility antigen and the major histocompatibility antigen by evaluating the affinity between the MHC long subsequence and the major histocompatibility antigen based on the calculated sum of the affinity information. Since the MHC binding partial sequence, which is an amino acid sequence that can be bound, is predicted, based on the affinity calculated statistically from the three-dimensional structure of the complex with MHC without depending on the information of known binding peptides, MHC binding subsequences that bind to and interact with specific major histocompatibility antigens can be predicted with high speed and high accuracy.

  Furthermore, the MHC binding partial sequence prediction method according to claim 40 is the MHC binding partial sequence prediction method according to claim 39, wherein the MHC long partial sequence creation step includes the purpose acquired by the target sequence acquisition step. The method further comprises a slide splitting step in which the sequence is divided into the length corresponding to the type of the major histocompatibility antigen while sliding the amino acid residue from the beginning to create the MHC long partial sequence. And

  This more specifically shows an example of the MHC length partial sequence creation step. According to this method, the MHC length partial sequence creation step divides the acquired target sequence into lengths corresponding to the types of major histocompatibility antigens while sliding one amino acid residue at a time from the beginning. Since the partial sequence is created, an MHC length partial sequence that may be divided can be created without omission.

  Furthermore, the MHC binding partial sequence prediction method according to claim 41 is the MHC binding partial sequence prediction method according to claim 39 or 40, wherein the length corresponding to the type of the major histocompatibility antigen is 8 The number of residues is ˜18.

  This is a more specific example of the length corresponding to the type of major histocompatibility antigen. According to this method, since the length corresponding to the type of major histocompatibility antigen is 8 to 18 residues, for example, it is 8 to 12 residues for MHC class I, and MHC class II On the other hand, since the number of residues can be 12-18, an MHC length partial sequence having an optimum length corresponding to each MHC type can be prepared.

  The MHC binding partial sequence prediction method according to claim 42 is the MHC binding partial sequence prediction method according to any one of claims 39 to 41, wherein the MHC binding partial sequence prediction method is determined by the major histocompatibility antigen determination step. Stores MHC-binding amino acid residue distance value information, which is information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen and each amino acid residue of the major histocompatibility antigen sequence. A step of storing a distance value between MHC-binding amino acid residues, wherein the affinity calculating step stores the affinity information as a distance value between the MHC-binding amino acid residues stored in the MHC-binding amino acid residue distance value storing step. Calculate using information and / or statistical potential using the 3D structure information of the known protein And further comprising a Hanarechi reference affinity calculating step.

  This more specifically shows an example of the affinity calculation step. According to this method, the MHC binding amino acid residue, which is information on the distance value between each amino acid residue of the amino acid sequence that binds to the determined major histocompatibility antigen and each amino acid residue of the major histocompatibility antigen sequence, is obtained. The group distance value information is stored, and the affinity calculation step uses the statistical potential using the stored MHC binding amino acid residue distance value information and / or the three-dimensional structure information of the known protein. Because it is calculated, it does not depend on the information of known binding peptides, and is specified based on the affinity calculated using the statistical potential using the distance between MHC-binding amino acid residues from the complex structure with MHC. MHC binding subsequences that bind to and interact with major histocompatibility antigens can be predicted at high speed and with high accuracy.

  In addition, the present invention relates to a program, and the program that causes a computer to execute the MHC binding partial sequence prediction method according to claim 43 is an amino acid sequence of a target protein or physiologically active polypeptide. It is determined by a target sequence acquisition step for acquiring target sequence information that is information on the target sequence, a main histocompatibility antigen determination step for determining the type of a specific main histocompatibility antigen, and the main histocompatibility antigen determination step. In addition, an MHC sequence acquisition step for acquiring main histocompatibility antigen sequence information, which is information on the main histocompatibility antigen sequence that is the amino acid sequence of the main histocompatibility antigen, and the purpose acquired by the target sequence acquisition step The major set determined by the major histocompatibility antigen determination step. An MHC length partial sequence creation step for creating an MHC length partial sequence by dividing into lengths corresponding to the types of compatible antigens, and each MHC length partial sequence created by the MHC length partial sequence creation step and the MHC Complex three-dimensional structure prediction step for predicting complex three-dimensional structure information based on the major histocompatibility antigen sequence acquired by the sequence acquisition step, and the complex three-dimensional structure predicted by the complex three-dimensional structure prediction step An interaction amino acid determination step for determining interaction amino acid information, which is information relating to the set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence, based on the information; Between the set of amino acids included in the interaction amino acid information determined by the interaction amino acid determination step Affinity calculation step for statistically calculating affinity information, which is information relating to affinity, using three-dimensional structure information of known proteins, and the affinity information between all the amino acid pairs calculated by the affinity calculation step An affinity sum total calculating step for calculating the sum of the above, and evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on the sum of the affinity information calculated by the affinity sum calculating step. And an affinity reference MHC binding partial sequence prediction step for predicting an MHC binding partial sequence that is the amino acid sequence capable of binding to the specific major histocompatibility antigen.

  According to this program, target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide, is obtained, a type of a specific major histocompatibility antigen is determined, and the determined major tissue Acquire major histocompatibility antigen sequence information, which is information on major histocompatibility antigen sequences that are amino acid sequences of compatible antigens, and obtain the target sequence length corresponding to the determined major histocompatibility antigen type To generate MHC long partial sequences, and based on each of the generated MHC long partial sequences and the obtained major histocompatibility antigen sequence, complex three-dimensional structure information is predicted, and the predicted complex three-dimensional structure Based on the structural information, interacting amino acid information that is information on the set of amino acids interacting between the MHC long subsequence and the major histocompatibility antigen sequence Affinity information, which is information on the affinity between amino acid pairs included in the determined interaction amino acid information, is statistically calculated using the three-dimensional structure information of known proteins, and all calculated By calculating the sum of affinity information between amino acid pairs and evaluating the affinity between the MHC long subsequence and the major histocompatibility antigen based on the calculated sum of affinity information, a specific major histocompatibility MHC binding partial sequence, which is an amino acid sequence that can bind to a sex antigen, is predicted, so the affinity calculated statistically from the three-dimensional structure of the complex with MHC does not depend on the information of known binding peptides. Based on this, it is possible to predict with high speed and high accuracy an MHC binding subsequence that binds to and interacts with a specific major histocompatibility antigen.

  Further, the program according to claim 44 is the program according to claim 43, wherein the MHC length partial sequence creation step includes: The method further comprises a slide dividing step of generating the MHC long partial sequence by sliding into the length corresponding to the type of the major histocompatibility antigen while sliding.

  This more specifically shows an example of the MHC length partial sequence creation step. According to this program, the MHC length partial sequence creation step divides the acquired target sequence into lengths corresponding to the types of major histocompatibility antigens while sliding one amino acid residue from the beginning, Since the partial sequence is created, an MHC length partial sequence that may be divided can be created without omission.

  The program according to claim 45 is the program according to claim 43 or 44, wherein the length corresponding to the type of the major histocompatibility antigen is 8 to 18 residues. And

  This is a more specific example of the length corresponding to the type of major histocompatibility antigen. According to this program, the length corresponding to the major histocompatibility antigen type is 8 to 18 residues, so for example, it is 8 to 12 residues for MHC class I and MHC class II. On the other hand, since the number of residues can be 12 to 18, it is possible to create an MHC length partial sequence having an optimum length corresponding to each MHC type.

  The program according to claim 46 is the amino acid that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determination step in the program according to any one of claims 43 to 45. MHC-binding amino acid residue distance value information storing MHC-binding amino acid residue distance value information, which is information regarding the distance value between each amino acid residue of the sequence and each amino acid residue of the major histocompatibility antigen sequence. The affinity calculation step further includes the step of storing the affinity information, the MHC-binding amino acid residue distance value information stored in the MHC-binding amino acid residue distance value storage step, and / or the known The distance value reference affinity calculation step is calculated using the statistical potential using the above three-dimensional structure information of the protein. Characterized in that it comprises in.

  This more specifically shows an example of the affinity calculation step. According to this program, the MHC binding amino acid residue, which is information on the distance value between each amino acid residue of the amino acid sequence that binds to the determined major histocompatibility antigen and each amino acid residue of the major histocompatibility antigen sequence, is determined. The group distance value information is stored, and the affinity calculation step uses the statistical potential using the stored MHC binding amino acid residue distance value information and / or the known three-dimensional structure information of the protein. Because it is calculated, it does not depend on the information of known binding peptides, and it is specified based on the affinity calculated using the statistical potential using the distance between MHC-binding amino acid residues from the 3D complex structure with MHC. MHC binding subsequences that bind to and interact with major histocompatibility antigens can be predicted with high speed and high accuracy.

  Further, the present invention relates to a recording medium, and the computer-readable recording medium according to claim 47 is characterized in that the program according to any one of claims 43 to 46 is recorded. .

  According to this recording medium, the program according to any one of claims 43 to 46 is realized using a computer by causing the computer to read and execute the program recorded on the recording medium. The same effect as each of these programs can be obtained.

  According to the present invention, from the target sequence information, 1) resistance to proteolytic enzymes or proteosomes present in lysosomes, 2) binding to MHC, 3) not recognized as self-peptides, 4) difficult to enter mutations A vaccine candidate partial sequence predicting apparatus, a vaccine candidate partial sequence predicting method capable of efficiently and accurately predicting a vaccine candidate partial sequence optimal as a vaccine that satisfies the four conditions and can activate T cells, Programs and recording media can be provided.

  In addition, according to the present invention, based on frequency analysis of cleavage site-containing sequences, non-cleaved partial sequences can be efficiently and highly accurately predicted by predicting enzyme cleavage sites by proteolytic enzymes or proteosomes present in lysosomes with high accuracy. It is possible to provide a vaccine candidate partial sequence prediction apparatus, a vaccine candidate partial sequence prediction method, a program, and a recording medium.

  In addition, according to the present invention, based on a motif search for a target sequence, an enzymatic cleavage site by a proteolytic enzyme or proteosome present in lysosome is predicted with high accuracy, thereby predicting an uncut partial sequence efficiently and with high accuracy. It is possible to provide a vaccine candidate partial sequence predicting apparatus, a vaccine candidate partial sequence predicting method, a program, and a recording medium.

  In addition, according to the present invention, based on the amino acid frequency analysis of known MHC binding site-containing sequences corresponding to various major histocompatibility antigens, MHC binding sites that bind to specific major histocompatibility antigens can be accurately obtained. By predicting, it is possible to provide a vaccine candidate partial sequence prediction apparatus, a vaccine candidate partial sequence prediction method, a program, and a recording medium that can efficiently and accurately predict an MHC binding partial sequence.

  In addition, according to the present invention, a motif is detected using known MHC binding site sequences corresponding to various major histocompatibility antigens, and binds to a specific major histocompatibility antigen based on the motif search. To provide a vaccine candidate partial sequence prediction apparatus, a vaccine candidate partial sequence prediction method, a program, and a recording medium that can predict an MHC binding partial sequence efficiently and with high accuracy by predicting an MHC binding site with high accuracy. it can.

  In addition, according to the present invention, it binds to a specific major histocompatibility antigen based on the affinity statistically calculated from the three-dimensional structure of the complex with MHC, without depending on information of a known binding peptide, It is possible to provide a vaccine candidate partial sequence prediction apparatus, a vaccine candidate partial sequence prediction method, a program, and a recording medium that can predict an interacting MHC binding partial sequence at high speed and with high accuracy.

  Moreover, according to the present invention, it is possible to provide a vaccine candidate partial sequence prediction apparatus, a vaccine candidate partial sequence prediction method, a program, and a recording medium that can create an MHC long partial sequence that may be divided without omission. it can.

  In addition, according to the present invention, there are provided a vaccine candidate partial sequence prediction apparatus, a vaccine candidate partial sequence prediction method, a program, and a recording medium capable of creating an MHC length partial sequence having an optimum length corresponding to each MHC type. can do.

  In addition, according to the present invention, the affinity calculated using a statistical potential using a distance between MHC-binding amino acid residues from a three-dimensional structure of a complex with MHC does not depend on information on a known binding peptide. -Based vaccine candidate partial sequence prediction apparatus, vaccine candidate partial sequence prediction method, program, and recording medium capable of predicting an MHC binding partial sequence that binds to and interacts with a specific major histocompatibility antigen at high speed and with high accuracy Can be provided.

  In addition, according to the present invention, a specific key is determined based on a structure evaluation index value calculated using a quantum chemistry calculation method for a three-dimensional structure of a complex with MHC, without depending on information on a known binding peptide. A vaccine candidate partial sequence prediction apparatus, a vaccine candidate partial sequence prediction method, a program, and a recording medium capable of efficiently and accurately predicting an MHC binding partial sequence that binds to and interacts with a histocompatibility antigen can be provided. .

  According to the present invention, non-self-recognizing partial sequences that are not recognized as self (having antigenicity) can be efficiently and highly accurately evaluated by evaluating whether they are recognized as self based on non-self-recognition search score information. It is possible to provide a vaccine candidate partial sequence predicting apparatus, a vaccine candidate partial sequence predicting method, a program, and a recording medium that can be predicted.

  Further, according to the present invention, it binds to a specific major histocompatibility antigen based on the affinity calculated statistically from the three-dimensional structure of the complex with MHC without depending on the information of known binding peptides. It is possible to provide an MHC binding partial sequence prediction apparatus, an MHC binding partial sequence prediction method, a program, and a recording medium that can predict an interacting MHC binding partial sequence with high speed and high accuracy.

  Furthermore, according to the present invention, it is possible to provide an MHC binding partial sequence prediction device, an MHC binding partial sequence prediction method, a program, and a recording medium that can create an MHC long partial sequence that may be divided without omission. it can.

  In addition, according to the present invention, there are provided an MHC binding partial sequence prediction apparatus, an MHC binding partial sequence prediction method, a program, and a recording medium capable of creating an MHC long partial sequence having an optimal length corresponding to each MHC type. can do.

  Furthermore, according to the present invention, the affinity calculated using the statistical potential using the distance between MHC-binding amino acid residues from the three-dimensional structure of the complex with MHC does not depend on the information of known binding peptides. MHC binding partial sequence prediction apparatus, MHC binding partial sequence prediction method, program, and recording medium capable of predicting MHC binding partial sequence that binds to and interacts with a specific major histocompatibility antigen at high speed and with high accuracy Can be provided.

  Hereinafter, embodiments of a vaccine candidate partial sequence prediction device, a vaccine candidate partial sequence prediction method, an MHC binding partial sequence prediction device, an MHC binding partial sequence prediction method, a program, and a recording medium according to the present invention will be described in detail with reference to the drawings. explain. Note that the present invention is not limited to the embodiments.

[Outline of the present invention]
Hereinafter, the outline of the present invention will be described, and then the configuration and processing of the present invention will be described in detail. FIG. 1 is a principle configuration diagram showing the basic principle of the present invention.

  The present invention generally has the following basic features.

  That is, according to the present invention, first, target sequence information that is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide is acquired and stored in a predetermined storage area of the target sequence file (step S-1). ).

  Next, from the target sequence information acquired in step S-1, an amino acid sequence that is not cleaved by a proteolytic enzyme or proteosome present in the lysosome and is a partial sequence of the target sequence (non-cleavable peptide) ) Is predicted and stored in a predetermined storage area of the uncut partial sequence file (step S-2).

  Here, in step S-2, the cleavage site-containing sequence information, which is information about the cleavage site-containing sequence, which is an amino acid sequence including several residues before and after the enzyme cleavage site, which is a site cleaved by a proteolytic enzyme, is stored. Calculate the cleavage site-containing sequence amino acid appearance frequency information, which is information on the appearance frequency of amino acids at positions corresponding to each amino acid residue in the stored cleavage site-containing sequence, and calculate the calculated cleavage site-containing sequence amino acid appearance frequency information. Based on the calculated cleavage site-containing sequence score information, each part obtained by dividing the target sequence obtained in step S-1 into the length of the cleavage site-containing sequence based on the calculated cleavage site-containing sequence score information Calculate the cleavage site-containing sequence length partial sequence score information corresponding to the sequence, and then calculate the enzyme based on the calculated cleavage site-containing sequence length partial sequence score information. Determining the cross-sectional site may predict the cut portions arranged in the enzyme cleavage site as non-cutting portion sequence (uncleaved peptide). In addition, each partial sequence which is the object of calculation of the cleavage site-containing sequence length partial sequence score information is a sequence of the cleavage site-containing sequence while sliding the target sequence obtained in step S-1 by one amino acid residue from the beginning. It may be created by dividing into lengths.

  Further, in step S-2, the cleavage site sequence information that is information on the cleavage site sequence that is the amino acid sequence of the enzyme cleavage site that is the site cleaved by the proteolytic enzyme is stored, and from the stored cleavage site sequence information, A known cleavage site motif sequence is extracted, and an enzyme cleavage site in the target sequence is searched by executing a motif search on the target sequence obtained in step S-1 using the extracted cleavage site motif sequence. Obtaining the cleavage site search score information that is the score at the time of search, determining the enzyme cleavage site of the target sequence based on the obtained cleavage site search score information, and removing the partial sequence cleaved at the enzyme cleavage site. It may be predicted as a cut partial sequence.

  Next, from the target sequence information obtained in step S-1, an amino acid sequence that can bind to a specific major histocompatibility antigen, which is a partial sequence of the target sequence, is predicted, The data is stored in a predetermined storage area of the MHC binding partial sequence file (step S-3).

  Here, in step S-3, the type of a specific major histocompatibility antigen is determined, and the amino acid sequence includes several residues before and after the MHC binding site, which is a site that binds to the determined major histocompatibility antigen. MHC binding site-containing sequence information, which is information related to the MHC binding site-containing sequence, is stored, and MHC binding site-containing information, which is information related to the appearance frequency of amino acids at positions corresponding to each amino acid residue in the stored MHC binding site-containing sequence Sequence amino acid appearance frequency information is calculated, based on the calculated MHC binding site-containing sequence amino acid appearance frequency information, MHC binding site-containing sequence score information is calculated, and based on the calculated MHC binding site-containing sequence score information, MHC binding site-containing sequence length corresponding to each partial sequence obtained by dividing the obtained target sequence into the length of the MHC binding site-containing sequence Calculates sequence score information, to determine the MHC-binding site on the basis of the calculated MHC binding site-containing sequence length partial sequence score information may predict a partial sequence including the MHC binding site as MHC binding subsequences. The length of the MHC binding site-containing sequence is calculated by dividing the obtained target sequence into the length of the sequence containing the MHC binding site while sliding the obtained target sequence by one amino acid residue from the beginning. It may be created.

  In step S-3, the type of a specific major histocompatibility antigen is determined, and information on the MHC binding site sequence, which is the amino acid sequence of the MHC binding site that is the site that binds to the determined major histocompatibility antigen. Stores certain MHC binding site sequence information, extracts a known MHC binding site motif sequence from the stored MHC binding site sequence information, and obtains it in step S-1 using the extracted MHC binding site motif sequence The MHC binding site in the target sequence is searched by executing a motif search on the target sequence obtained, MHC binding site search score information that is a score at the time of search is obtained, and the acquired MHC binding site search score information Based on this, an MHC binding site may be determined, and a partial sequence including the MHC binding site may be predicted as an MHC binding partial sequence.

  In step S-3, the type of a specific major histocompatibility antigen is determined, and the major histocompatibility antigen sequence which is information on the major histocompatibility antigen sequence that is the amino acid sequence of the determined major histocompatibility antigen. Information is acquired, the target sequence acquired in step S-1 is divided into lengths corresponding to the determined major histocompatibility antigen types, MHC length partial sequences are generated, and each MHC generated Based on the long partial sequence and the obtained major histocompatibility antigen sequence, complex tertiary structure information is predicted, and based on the predicted complex tertiary structure information, the MHC long partial sequence and the major histocompatibility antigen sequence are Information on interaction amino acids that are information on amino acid pairs interacting with each other, and information on affinity between amino acid sets included in the determined interaction amino acid information. Affinity information is statistically calculated using the three-dimensional structure information of known proteins, the sum of affinity information between all calculated amino acid pairs is calculated, and based on the calculated sum of affinity information Thus, the MHC binding partial sequence may be predicted by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen.

  The target sequence may be divided into lengths corresponding to the determined types of major histocompatibility antigens by sliding one amino acid residue from the beginning to create an MHC long partial sequence. The length corresponding to the type of major histocompatibility antigen may be, for example, 8 to 18 residues. Further, the distance value between MHC-binding amino acid residues, which is information on the distance value between each amino acid residue of the amino acid sequence that binds to the determined major histocompatibility antigen and each amino acid residue of the major histocompatibility antigen sequence Information may be stored, and affinity information may be calculated using the stored MHC binding amino acid residue distance value information and / or statistical potential using known protein conformation information.

  In step S-3, the type of the specific major histocompatibility antigen is determined, MHC three-dimensional structure information which is the determined three-dimensional structure of the main histocompatibility antigen is obtained, and the obtained MHC three-dimensional structure information and Based on the acquired partial sequence of the target sequence, complex 3D structure information of the major histocompatibility antigen and the partial sequence is created, and in the created complex 3D structure information, a quantum chemical calculation method (for example, inexperienced Structure evaluation index value information, which is information related to index values for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information, using a molecular orbital method, semi-empirical molecular orbital method, MOZYME method, etc. An MHC binding partial sequence may be predicted from the partial sequences based on the structured evaluation index value information. The partial sequence may be created by dividing the target sequence obtained in step S-1 while sliding it by one amino acid residue from the beginning.

  The structure evaluation index value information includes, for example, a semi-empirical molecular orbital calculation program “MOPAC2000” (product name) (Fujitsu Ltd. (company name)) that implements the MOZYME method, and an ab initio molecular orbital method. Implemented molecular orbital calculation program “Gaussian 98 Rev. A. 11.3” (product name) (Gaussian, Inc. (company name), Pittsburgh PA. 2002) and “Gamess June 20 2002 R2” (product name) (Iowa) State University, 2002) may be a value obtained as a result of energy calculation.

  Next, a non-self-recognizing partial sequence that is an amino acid sequence that is not recognized as self and is a partial sequence of the target sequence is predicted from the target sequence information acquired in step S-1, and a predetermined non-self-recognizing partial sequence file is stored. (Step S-4).

  Here, in step S-4, the specific biological species sequence information that is information related to the specific biological species amino acid sequence that is an amino acid sequence related to a specific biological species (for example, human) is stored, and the stored specific biological species sequence information is stored. In contrast, by performing a search of the partial sequence of the acquired target sequence, non-self-recognition search score information that is a score at the time of search is acquired, and based on the acquired non-self-recognition search score information, a partial A non-self-recognizing partial sequence may be predicted from the sequence. The partial sequence may be created by dividing the target sequence obtained in step S-1 while sliding it by one amino acid residue from the beginning.

  In step S-4, a non-self-recognizing partial sequence may be predicted using the technique described in Japanese Patent Application No. 2003-129554, which is a patent application filed by the present applicant.

  Next, from the target sequence information acquired in step S-1, an unmutated partial sequence that is an amino acid sequence that is difficult to mutate and is a partial sequence of the target sequence is predicted. The data is stored in a predetermined storage area (step S-5).

  Here, in step S-5, a mutation prediction method for predicting a mutation probability (for example, a probability of causing a mutation for each partial sequence of the target sequence acquired in step S-1) (for example, (See the patent publication “Patent No. 312957”), and a mutation probability is predicted, and a non-mutated partial sequence is predicted from among the partial sequences based on the predicted mutation probability. Good. The partial sequence may be created by dividing the target sequence obtained in step S-1 while sliding it by one amino acid residue from the beginning.

  Here, the technique described in the patent publication “Patent No. 3102957” utilizes the fact that point mutations depend on local partial sequences. Specifically, an error spectrum that is a set of mutation probabilities for each base in a DNA partial sequence is synthesized for a character string (a combination of four letters A, C, G, and T) to be predicted, By calculating the sum of the mutation probabilities, a base having a high sum is predicted to have a high probability of causing a mutation, thereby enabling prediction of gene mutation.

  Then, the non-cleavable partial sequence predicted in step S-2, the MHC binding partial sequence predicted in step S-3, the non-self-recognizing partial sequence predicted in step S-4, and / or the step Based on the non-mutated partial sequence predicted in S-5, a vaccine candidate partial sequence that is an amino acid sequence effective as a vaccine is predicted and stored in a predetermined storage area of the vaccine candidate partial sequence file (step S- 6).

  Here, in step S-6, for example, at least one of the cleavage site-containing sequence length partial sequence score information and the cleavage site search score information calculated in step S-2, calculated in step S-3 At least one of MHC binding site-containing sequence length partial sequence score information, MHC binding site search score information, sum of affinity information, structure evaluation index value information, non-self recognition search score information calculated in step S-4, A linear sum of mutation probabilities calculated in step S-5 may be calculated, and a vaccine candidate partial sequence may be predicted based on the calculated linear sum. That is, the likelihood of peptide vaccine may be scored to take a linear sum, and a vaccine candidate partial sequence may be predicted based on the linear sum. Specifically, for example, a partial sequence having a high overall score may be predicted as a vaccine candidate partial sequence.

  As mentioned above, in the outline | summary of this invention, although the case where the process of step S-2-step S-5 was performed in parallel was demonstrated to an example, for example, step S-2, step S-3, step S-4, step By processing in series in the order of S-5, candidates for partial sequences of the target sequence may be sequentially narrowed down, and finally the remaining partial sequences may be predicted as vaccine candidate partial sequences. Specifically, for example, among the partial sequences predicted in step S-2, for example, the lower order (for example, the set corresponding to the lower 80%) is excluded from the candidates for amino acid sequences effective as vaccines and narrowed down. The partial sequence of the remaining set (for example, upper 20%) proceeds to step S-3, and for example, the lower sequence (for example, the set corresponding to the lower 80%) of the partial sequence predicted in step S-3 is vaccine. Are further excluded from the candidates of effective amino acid sequences, and the final narrowed partial set (for example, the top 4%) of the partial sequences proceeds to steps S-4 and S-5 to predict vaccine candidate partial sequences. May be. In other words, by setting exclusion criteria (adoption criteria) to exclude (or adopt as peptide vaccine candidates) from peptide vaccine candidates at each step, a partial sequence that finally satisfies all exclusion criteria (adoption criteria) May be predicted as a vaccine candidate partial sequence.

[System configuration]
Next, the configuration of this system will be described. FIG. 2 is a block diagram showing an example of the configuration of the system to which the present invention is applied, and conceptually shows only the portion related to the present invention in the configuration. This system roughly includes a vaccine candidate partial sequence prediction apparatus 100 and an external system 200 that provides an external database relating to amino acid sequences and three-dimensional structures of proteins, external programs such as motif search and homology search, and the like. It is configured to be communicably connected via 300.

  In FIG. 2, the network 300 has a function of connecting the vaccine candidate partial sequence prediction device 100 and the external system 200 to each other, and is, for example, the Internet.

  In FIG. 2, the external system 200 is connected to the vaccine candidate partial sequence prediction apparatus 100 via the network 300, and provides an external database regarding amino acid sequences and three-dimensional structures of proteins, motif search, and homology search to the user. And a function of providing a website for executing an external program.

  Here, the external system 200 may be configured as a WEB server, an ASP server, or the like, and the hardware configuration may be configured by an information processing apparatus such as a commercially available workstation or a personal computer and an accessory device thereof. Good. Each function of the external system 200 is realized by a CPU, a disk device, a memory device, an input device, an output device, a communication control device, and the like in the hardware configuration of the external system 200 and a program for controlling them.

  In FIG. 2, the vaccine candidate partial sequence prediction apparatus 100 schematically includes a control unit 102 such as a CPU that controls the entire vaccine candidate partial sequence prediction apparatus 100 and a communication device such as a router connected to a communication line or the like. A communication control interface unit 104 connected to (not shown), an input / output control interface unit 108 connected to the input device 112 and the output device 114, and a storage unit 106 for storing various databases and tables. These parts are configured to be communicable via an arbitrary communication path. Further, the vaccine candidate partial sequence prediction device 100 is communicably connected to the network 300 via a communication device such as a router and a wired or wireless communication line such as a dedicated line.

  Various databases and tables (target sequence file 106a to vaccine candidate partial sequence file 106f) stored in the storage unit 106 are storage means such as a fixed disk device, and as shown in FIG. Stores programs, tables, files, databases, web page files, etc. FIG. 3 is a diagram showing an example of information stored in the storage unit 106 of the present system to which the present invention is applied.

  As shown in FIG. 3, among these components of the storage unit 106, the target sequence file 106a stores the target sequence information that is information on the target sequence that is the amino acid sequence of the target protein or physiologically active polypeptide. It is an array storage means. The information stored in the target sequence file 106a is composed of target sequence information.

  The cleavage site-containing sequence file 106b1 stores cleavage site-containing sequence information that is information on a cleavage site-containing sequence that is an amino acid sequence including several residues before and after the enzyme cleavage site, which is a site that is cleaved by a proteolytic enzyme. It is a cutting site containing sequence storage means. The information stored in the cleavage site-containing sequence file 106b1 includes, for example, a total of 12 residues including 6 residues before and after P1 and P1 ′, which are enzyme cleavage sites, as shown in FIG. It consists of the amino acid sequence of the residues.

  The cleavage site-containing sequence amino acid appearance frequency file 106b2 contains a cleavage site-containing sequence amino acid appearance frequency information that is information on the appearance frequency of amino acids at positions corresponding to the respective amino acid residues in the cleavage site-containing sequence. It is a sequence amino acid appearance frequency storage means. The information stored in this cleavage site-containing sequence amino acid appearance frequency file 106b2 includes, for example, six residues before and after P1 and P1 ′, which are enzyme cleavage sites, as shown in FIG. 20 types of amino acids (A, C, D,..., V, W, Y) at positions (P6 to P1 and P1 ′ to P6 ′) corresponding to each amino acid residue of a total of 12 amino acid sequences including It is composed of the appearance frequency.

  The cleavage site-containing sequence score file 106b3 stores the cleavage site-containing sequence score storage means for storing the cleavage site-containing sequence score information, which is information obtained by converting each appearance frequency in the cleavage site-containing sequence amino acid appearance frequency information into a score (score). It is. The information stored in this cleavage site-containing sequence score file 106b3 includes, for example, a total of 6 residues before and after P1 and P1 ′, which are enzyme cleavage sites, as shown in FIG. 24 referred to in this example. Scores of 20 kinds of amino acids (A, C, D,..., V, W, Y) at positions (P6 to P1 and P1 ′ to P6 ′) corresponding to each amino acid residue of the 12-residue amino acid sequence (Score).

  The cleavage site-containing sequence length partial sequence file 106b4 is a cleavage site-containing sequence length partial sequence storage means for storing a cleavage site-containing sequence length partial sequence that is a partial sequence obtained by dividing the target sequence into the length of the cleavage site-containing sequence. is there. The information stored in the cleavage site-containing sequence length partial sequence file 106b4 includes the cleavage site-containing sequence length partial sequence and the cleavage site-containing sequence length partial sequence score, which are partial sequences obtained by dividing the target sequence into the length of the cleavage site-containing sequence. It is configured to correlate with information.

  The cleavage site sequence file 106b5 is a cleavage site sequence storage means for storing cleavage site sequence information that is information relating to a cleavage site sequence that is an amino acid sequence of an enzyme cleavage site that is a site cleaved by a proteolytic enzyme. The information stored in the cleavage site sequence file 106b5 includes, for example, the amino acid sequences of P1 and P1 ′ that are enzyme cleavage sites (see, for example, P2 as shown in FIG. 22). , P1, and P1 ′ amino acid sequences are included.).

  The cleavage site motif sequence file 106b6 is a cleavage site motif sequence storage means for storing a known cleavage site motif sequence extracted from the cleavage site sequence information. The information stored in the cleavage site motif sequence file 106b6 includes, for example, the cleavage site motif sequences (EY, FA, FF,..., RR, VLS, WMRFA, ...).

  In addition, the cleavage site search score file 106b7 is a search score obtained by searching for an enzyme cleavage site in the target sequence by performing a motif search on the target sequence acquired using the cleavage site motif sequence. This is a cutting site search score storage means for storing cutting site search score information. The information stored in the cut site search score file 106b7 is composed of cut site search score information corresponding to each cut site motif sequence.

  The non-cleavable partial sequence file 106b8 is an amino acid sequence that is not cleaved by a proteolytic enzyme or proteosome present in the lysosome and is a non-cleavable partial sequence storage means for storing a non-cleavable partial sequence that is a partial sequence of the target sequence. is there. The information stored in the non-cut partial sequence file 106b8 includes a non-cut partial sequence that is a partial sequence cut at the determined enzyme cleavage site.

  The MHC binding site-containing sequence file 106c1 is an MHC binding site-containing sequence that is information on an MHC binding site-containing sequence that is an amino acid sequence including several residues before and after the MHC binding site that is a site that binds to a major histocompatibility antigen. MHC binding site-containing sequence storage means for storing information. The information stored in the MHC binding site-containing sequence file 106c1 is composed of an amino acid sequence of a total of 8 residues including the MHC binding site, for example, as shown in FIG.

  The MHC binding site-containing sequence amino acid appearance frequency file 106c2 stores MHC binding site-containing sequence amino acid appearance frequency information, which is information regarding the appearance frequency of amino acids at positions corresponding to each amino acid residue in the MHC binding site-containing sequence. MHC binding site-containing sequence amino acid appearance frequency storage means. The information stored in the MHC binding site-containing sequence amino acid appearance frequency file 106c2 includes 20 types of information at positions (for example, B1 to B8 in FIGS. 28 and 29) corresponding to each amino acid residue of the MHC binding site-containing sequence. It consists of the appearance frequency of amino acids (A, C, D,..., V, W, Y).

  The MHC binding site-containing sequence score file 106c3 stores MHC binding site-containing sequence score information that is information obtained by converting each appearance frequency in the MHC binding site-containing sequence amino acid appearance frequency information into a score (score). This is an array score storage means. The information stored in the MHC binding site-containing sequence score file 106c3 includes, for example, positions (B1 to B8) corresponding to each amino acid residue of the MHC binding site-containing sequence as shown in FIG. 29 referred to in the present example. Is composed of scores (scores) of 20 types of amino acids (A, C, D,..., V, W, Y).

  The MHC binding site-containing sequence length partial sequence file 106c4 stores an MHC binding site-containing sequence length partial sequence, which is a partial sequence obtained by dividing the target sequence into the length of the MHC binding site-containing sequence. It is an array storage means. The information stored in the MHC binding site-containing sequence length partial sequence file 106c4 includes the MHC binding site-containing sequence length partial sequence and the MHC binding site-containing sequence, which are partial sequences obtained by dividing the target sequence into the length of the MHC binding site-containing sequence. The long partial sequence score information is associated with each other.

  The MHC binding site sequence file 106c5 stores an MHC binding site sequence information that stores MHC binding site sequence information that is information on the MHC binding site sequence that is the amino acid sequence of the MHC binding site that is a site that binds to the major histocompatibility antigen. Means. The information stored in the MHC binding site sequence file 106c5 is composed of an amino acid sequence of an MHC binding site that is a site that binds to a major histocompatibility antigen.

  The MHC binding site motif sequence file 106c6 is MHC binding site motif sequence storage means for storing a known MHC binding site motif sequence extracted from MHC binding site sequence information. The information stored in the MHC binding site motif sequence file 106c6 includes, for example, an MHC binding site motif sequence (Axxx indicated by hatching in FIG. 28, as shown in FIG. 28 referred to in this example). It is composed of amino acid sequences such as AA, AxxxF, and Axxx I ("x" is any amino acid)).

  In addition, the MHC binding site search score file 106c7 is used when searching for an MHC binding site in a target sequence by performing a motif search on the target sequence acquired using the MHC binding site motif sequence. MHC binding site search score storage means for storing MHC binding site search score information that is a score of The information stored in the MHC binding site search score file 106c7 is composed of MHC binding site search score information corresponding to each MHC binding site motif sequence.

  The MHC sequence file 106c8 is MHC sequence storage means for storing main histocompatibility antigen sequence information which is information relating to the main histocompatibility antigen sequence which is the amino acid sequence of the main histocompatibility antigen. The information stored in the MHC sequence file 106c8 is configured by associating the type of main histocompatibility antigen with the main histocompatibility antigen sequence information.

  The MHC length partial sequence file 106c9 is MHC length partial sequence storage means for storing an MHC length partial sequence that is an amino acid sequence obtained by dividing the target sequence into lengths corresponding to the determined major histocompatibility antigen types. is there. The information stored in the MHC long partial sequence file 106c9 is composed of an MHC long partial sequence having a length corresponding to the determined major histocompatibility antigen type.

  The predicted complex three-dimensional structure file 106c10 is a predicted complex three-dimensional structure storage unit that stores complex three-dimensional structure information predicted based on each MHC long partial sequence and major histocompatibility antigen sequence. The information stored in the predicted complex 3D structure file 106c10 is composed of complex 3D structure information.

  The interaction amino acid file 106c11 is interaction amino acid storage means for storing interaction amino acid information, which is information regarding a set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence. . The information stored in the interaction amino acid file 106c11 is configured by associating interacting amino acids with each other.

  The affinity file 106c12 is an affinity storage unit that stores affinity information, which is information related to the affinity between amino acid sets included in the interacting amino acid information. The information stored in the affinity file 106c12 is configured by associating a set of amino acids with affinity information.

  The distance value file 106c13 between MHC-binding amino acid residues is information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen and each amino acid residue of the major histocompatibility antigen sequence. It is a distance value storage means for storing MHC-linked amino acid residue distance value information for storing information on the distance value between MHC-linked amino acid residues. The information stored in the distance value file 106c13 between the MHC-binding amino acid residues is composed of distance values between amino acid residues as shown in FIG. 32 referred to in the present embodiment, for example.

  The MHC three-dimensional structure file 106c14 is MHC three-dimensional structure storage means for storing MHC three-dimensional structure information that is the three-dimensional structure of the main histocompatibility antigen. The information stored in the MHC three-dimensional structure file 106c14 includes, for example, information on the three-dimensional structure (crystal structure) of the major histocompatibility antigen (the crystal structure shown in FIG. 33) as shown in FIG. The data is a part.)

  The created complex 3D structure file 106c15 stores a created complex 3D structure that stores the 3D structure information of the major histocompatibility antigen and the partial sequence created based on the MHC 3D structure information and the partial sequence of the target sequence. Storage means. The information stored in the created complex three-dimensional structure file 106c15 is composed of complex three-dimensional structure information of major histocompatibility antigens and partial sequences.

  The structure evaluation index value file 106c16 is a structure evaluation index value storage unit that stores structure evaluation index value information that is information related to an index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information. The information stored in the structure evaluation index value file 106c16 includes structure evaluation index value information that is information regarding index values for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information.

  The MHC binding partial sequence file 106c17 is an MHC binding partial sequence storage means for storing an MHC binding partial sequence that is an amino acid sequence that can bind to a specific major histocompatibility antigen and is a partial sequence of the target sequence. is there. The information stored in the MHC binding partial sequence file 106c17 is composed of an MHC binding partial sequence.

  The specific species sequence file 106d1 is a specific species sequence storage unit that stores specific species sequence information, which is information related to the specific species amino acid sequence, which is an amino acid sequence related to the specific species. The information stored in this specific species sequence file 106d1, for example, is composed of an amino acid sequence relating to a known specific species (in FIG. 36, a human amino acid sequence) as shown in FIG. Has been.

  Further, the non-self-recognition search score file 106d2 stores non-self-recognition search score information, which is a score at the time of search, obtained by executing a partial sequence search of the target sequence with respect to the specific species sequence information. Non-self-recognizing search score storage means. The information stored in the non-self-recognized search score file 106d2 includes non-self-recognized search score information corresponding to the partial sequence.

  The non-self-recognizing partial sequence file 106d3 is non-self-recognizing partial sequence storage means for storing a non-self-recognizing partial sequence that is an amino acid sequence that is not recognized as self and that is a partial sequence of the target sequence. The information stored in the non-self-recognizing partial sequence file 106d3 includes a non-self-recognizing partial sequence.

  The mutation probability file 106e1 stores mutation probabilities predicted based on a mutation prediction method for predicting a mutation probability that is a probability of causing mutation for each partial sequence of the target sequence. It is a mutation probability storage means. The information stored in the mutation probability file 106e1 is composed of mutation probabilities corresponding to the partial sequences.

  Further, the non-mutated partial sequence file 106e2 is a non-mutated partial sequence storage means for storing a non-mutated partial sequence that is an amino acid sequence that is difficult to be mutated and is a partial sequence of the target sequence. The information stored in the non-mutant partial sequence file 106e2 is composed of a non-mutant partial sequence.

  The vaccine candidate partial sequence file 106f is a vaccine candidate partial sequence means for storing a vaccine candidate partial sequence that is an amino acid sequence effective as a vaccine. The information stored in the vaccine candidate partial sequence file 106f is composed of vaccine candidate partial sequences.

  In FIG. 2, the communication control interface unit 104 performs communication control between the vaccine candidate partial sequence prediction device 100 and the network 300 (or a communication device such as a router). That is, the communication control interface unit 104 has a function of communicating data with other terminals via a communication line.

  In FIG. 2, the input / output control interface unit 108 controls the input device 112 and the output device 114. Here, as the output device 114, in addition to a monitor (including a home TV), a speaker or the like can be used (hereinafter, the output device 114 may be described as a monitor). As the input device 112, a keyboard, a mouse, a microphone, or the like can be used. The monitor also realizes a pointing device function in cooperation with the mouse.

  In FIG. 2, the control unit 102 has a control program such as an OS (Operating System), a program defining various processing procedures, and an internal memory for storing necessary data. Information processing for executing various processes is performed. In terms of functional concept, the control unit 102 includes a target sequence acquisition unit 102a, a non-cut partial sequence prediction unit 102b, an MHC binding partial sequence prediction unit 102c, a non-self recognition partial sequence prediction unit 102d, a non-mutation partial sequence prediction unit 102e, and A vaccine candidate partial sequence predicting unit 102f is included.

  Among these, the target sequence acquisition unit 102a is target sequence acquisition means for acquiring target sequence information, which is information related to the target sequence, which is the amino acid sequence of the target protein or physiologically active polypeptide.

  Further, the non-cleavable partial sequence predicting unit 102b is an amino acid sequence that is not cleaved by a proteolytic enzyme or proteosome present in the lysosome from the target sequence information, and predicts a non-cut partial sequence that is a partial sequence of the target sequence. This is a cut partial sequence predicting means. Here, as shown in FIG. 4, the non-cut partial sequence predicting unit 102b includes a cut site containing sequence storage unit 102b1, a cut site containing sequence amino acid appearance frequency calculating unit 102b2, a cut site containing sequence score calculating unit 102b3, and a cut site containing Sequence length partial sequence score calculation unit 102b4, score reference non-cut partial sequence prediction unit 102b5, cut site sequence storage unit 102b6, cut site motif sequence extraction unit 102b7, cut site motif search unit 102b8 and motif search reference non-cut partial sequence prediction unit 102b9 is further provided.

  FIG. 4 is a block diagram showing an example of the configuration of the non-cut partial sequence predicting unit 102b of the system to which the present invention is applied, and conceptually shows only the portion related to the present invention. In FIG. 4, the cleavage site-containing sequence storage unit 102b1 is information on a cleavage site-containing sequence that is information on a cleavage site-containing sequence that is an amino acid sequence including several residues before and after the enzyme cleavage site, which is a site cleaved by a proteolytic enzyme. Is a cutting site-containing sequence storage means for storing.

  In addition, the cleavage site-containing sequence amino acid appearance frequency calculation unit 102b2 calculates a cleavage site-containing sequence amino acid appearance frequency information that is information on the appearance frequency of amino acids at positions corresponding to each amino acid residue in the cleavage site-containing sequence. This is means for calculating the frequency of occurrence of amino acids in the contained sequence.

  The cleavage site-containing sequence score calculation unit 102b3 is a cleavage site-containing sequence score calculation unit that calculates cleavage site-containing sequence score information based on the cleavage site-containing sequence amino acid appearance frequency information.

  In addition, the cleavage site-containing sequence length partial sequence score calculation unit 102b4 includes a cleavage site corresponding to each partial sequence obtained by dividing the acquired target sequence into the length of the cleavage site-containing sequence based on the cleavage site-containing sequence score information. This is a cleavage site-containing sequence length partial sequence score calculation means for calculating sequence length partial sequence score information.

  Further, the score criterion non-cutting partial sequence predicting unit 102b5 determines an enzyme cutting site based on the cutting site-containing sequence length partial sequence score information, and predicts a partial sequence cut at the enzyme cutting site as a non-cutting partial sequence. This is a score-based non-cutting partial sequence predicting means.

  The cleavage site sequence storage unit 102b6 is a cleavage site sequence storage means for storing cleavage site sequence information, which is information relating to a cleavage site sequence that is an amino acid sequence of an enzyme cleavage site that is a site cleaved by a proteolytic enzyme.

  The cleavage site motif sequence extraction unit 102b7 is a cleavage site motif sequence extraction unit that extracts a known cleavage site motif sequence from the cleavage site sequence information.

  The cleavage site motif search unit 102b8 searches for an enzyme cleavage site in the target sequence by performing a motif search on the target sequence obtained using the cleavage site motif sequence, and the cleavage that is the score at the time of the search This is a cutting site motif search means for acquiring site search score information.

  The motif search reference non-cleavable partial sequence prediction unit 102b9 determines an enzyme cleavage site of the target sequence based on the cleavage site search score information, and predicts a partial sequence cleaved at the enzyme cleavage site as an uncut partial sequence. This is a motif search reference non-cut partial sequence prediction means.

  Returning to FIG. 2 again, the MHC binding partial sequence prediction unit 102c is an amino acid sequence that can bind to a specific major histocompatibility antigen from the target sequence information, and is an MHC binding partial sequence that is a partial sequence of the target sequence. Is a means for predicting MHC binding partial sequences. Here, as shown in FIG. 5, the MHC binding partial sequence predicting unit 102 c includes a major histocompatibility antigen determining unit 102 c 1, an MHC binding site-containing sequence storage unit 102 c 2, an MHC binding site-containing sequence amino acid appearance frequency calculating unit 102 c 3, and an MHC. Binding site-containing sequence score calculation unit 102c4, MHC binding site-containing sequence length partial sequence score calculation unit 102c5, score reference MHC binding partial sequence prediction unit 102c6, MHC binding site sequence storage unit 102c7, MHC binding site motif sequence extraction unit 102c8, MHC Binding site motif search unit 102c9, motif search reference MHC binding partial sequence prediction unit 102c10, MHC sequence acquisition unit 102c11, MHC long partial sequence creation unit 102c12, slide division unit 102c13, complex three-dimensional structure prediction unit 102c14, interacting amino acid determination unit 102 15, MHC binding amino acid residue distance value storage unit 102c16, affinity calculation unit 102c17, distance value reference affinity calculation unit 102c18, affinity sum calculation unit 102c19, affinity reference MHC binding partial sequence prediction unit 102c20, MHC three-dimensional structure acquisition unit 102c21, A complex three-dimensional structure creation unit 102c22, a structure evaluation index calculation unit 102c23, and a structure evaluation index reference MHC binding partial sequence prediction unit 102c24 are further provided.

  FIG. 5 is a block diagram showing an example of the configuration of the MHC binding partial sequence predicting unit 102c of the present system to which the present invention is applied, and conceptually shows only the portion related to the present invention. In FIG. 5, a main histocompatibility antigen determination unit 102c1 is a main histocompatibility antigen determination unit that determines the type of a specific main histocompatibility antigen.

  In addition, the MHC binding site-containing sequence storage unit 102c2 includes an MHC binding site-containing information that is information on an MHC binding site-containing sequence that is an amino acid sequence including several residues before and after the MHC binding site that is a site that binds to a major histocompatibility antigen. MHC binding site-containing sequence storage means for storing sequence information.

  In addition, the MHC binding site-containing sequence amino acid appearance frequency calculation unit 102c3 calculates MHC binding site-containing sequence amino acid appearance frequency information, which is information regarding the appearance frequency of amino acids at positions corresponding to each amino acid residue in the MHC binding site-containing sequence. MHC binding site-containing sequence amino acid appearance frequency calculation means.

  The MHC binding site-containing sequence score calculation unit 102c4 is MHC binding site-containing sequence score calculation means for calculating MHC binding site-containing sequence score information based on the MHC binding site-containing sequence amino acid appearance frequency information.

  The MHC binding site-containing sequence length partial sequence score calculation unit 102c5 corresponds to each partial sequence obtained by dividing the acquired target sequence into the length of the MHC binding site-containing sequence based on the MHC binding site-containing sequence score information. MHC binding site-containing sequence length partial sequence score calculation means for calculating MHC binding site-containing sequence length partial sequence score information.

  In addition, the score reference MHC binding partial sequence predicting unit 102c6 determines an MHC binding site based on the MHC binding site-containing sequence length partial sequence score information, and a score for predicting a partial sequence including the MHC binding site as an MHC binding partial sequence Reference MHC binding partial sequence prediction means.

  In addition, the MHC binding site sequence storage unit 102c7 stores MHC binding site sequence information, which is information related to the MHC binding site sequence that is the amino acid sequence of the MHC binding site that is a site that binds to the major histocompatibility antigen. Storage means.

  The MHC binding site motif sequence extraction unit 102c8 is MHC binding site motif sequence extraction means for extracting a known MHC binding site motif sequence from the MHC binding site sequence information.

  The MHC binding site motif search unit 102c9 searches for an MHC binding site in the target sequence by executing a motif search on the target sequence obtained using the MHC binding site motif sequence, and uses the score at the time of the search. This is an MHC binding site motif search means for acquiring certain MHC binding site search score information.

  The motif search reference MHC binding partial sequence prediction unit 102c10 determines an MHC binding site based on the MHC binding site search score information and predicts a partial sequence including the MHC binding site as an MHC binding partial sequence. This is a binding partial sequence predicting means.

  The MHC sequence acquisition unit 102c11 is MHC sequence acquisition means for acquiring main histocompatibility antigen sequence information, which is information relating to the main histocompatibility antigen sequence, which is the amino acid sequence of the main histocompatibility antigen.

  The MHC length partial sequence creation unit 102c12 is MHC length partial sequence creation means for creating an MHC length partial sequence by dividing the target sequence into lengths corresponding to the determined types of major histocompatibility antigens.

  The slide dividing unit 102c13 is a slide dividing unit that divides the target sequence into lengths corresponding to the types of major histocompatibility antigens while sliding the amino acid residues one by one from the beginning, and creates an MHC long partial sequence. is there.

  The complex three-dimensional structure prediction unit 102c14 is a complex three-dimensional structure prediction unit that predicts complex three-dimensional structure information based on each MHC long partial sequence and the main histocompatibility antigen sequence acquired by the MHC sequence acquisition unit. is there.

  Further, the interacting amino acid determination unit 102c15 is based on the complex three-dimensional structure information, and interacting amino acid information that is information regarding the set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence. It is a means for determining interacting amino acids.

  The distance value storage unit 102c16 between MHC-binding amino acid residues is information on the distance value between each amino acid residue of the amino acid sequence that binds to the main histocompatibility antigen and each amino acid residue of the main histocompatibility antigen sequence. MHC-binding amino acid residue distance value storage means for storing MHC-binding amino acid residue distance value information.

  The affinity calculator 102c17 is an affinity calculator that statistically calculates affinity information, which is information related to the affinity between amino acid sets included in the interacting amino acid information, using the three-dimensional structure information of known proteins. is there.

  In addition, the distance value reference affinity calculation unit 102c18 calculates the affinity information using the stored MHC-binding amino acid residue distance value information and / or the statistical potential using the known three-dimensional structure information of the protein. It is a value-based affinity calculation means.

  The affinity sum calculation unit 102c19 is an affinity sum calculation means for calculating the sum of affinity information between all amino acid pairs.

  Further, the affinity reference MHC binding partial sequence predicting unit 102c20 evaluates the affinity between the MHC long partial sequence and the main histocompatibility antigen based on the sum of the affinity information, and thereby the affinity reference for predicting the MHC binding partial sequence. MHC binding partial sequence prediction means.

  The MHC three-dimensional structure acquisition unit 102c21 is an MHC three-dimensional structure acquisition unit that acquires MHC three-dimensional structure information that is the three-dimensional structure of the main histocompatibility antigen.

  The complex three-dimensional structure creation unit 102c22 creates complex three-dimensional structure information of the major histocompatibility antigen and the partial sequence based on the MHC three-dimensional structure information and the acquired partial sequence of the target sequence. It is a creation means.

  In addition, the structure evaluation index calculation unit 102c23 is structure evaluation index value information that is information regarding an index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information using the quantum chemistry calculation method in the three-dimensional structure information of the complex. This is a structure evaluation index calculation means for calculating.

  The structure evaluation index reference MHC binding partial sequence prediction unit 102c24 is a structure evaluation index reference MHC binding partial sequence prediction unit that predicts an MHC binding partial sequence from the partial sequences based on the structure evaluation index value information.

  Returning to FIG. 2 again, the non-self-recognizing partial sequence predicting unit 102d predicts a non-self-recognizing partial sequence that is an amino acid sequence that is not recognized as self from the target sequence information and that is a partial sequence of the target sequence. This is a sequence prediction means. Here, as shown in FIG. 6, the non-self-recognizing partial sequence prediction unit 102d further includes a specific species sequence storage unit 102d1, a non-self-recognizing partial sequence search unit 102d2, and a search reference non-self-recognizing partial sequence prediction unit 102d3. Configured.

  FIG. 6 is a block diagram showing an example of the configuration of the non-self-recognizing partial sequence prediction unit 102d of the present system to which the present invention is applied, and conceptually shows only the portion related to the present invention. . In FIG. 6, a specific species sequence storage unit 102d1 is a specific species sequence storage means for storing specific species sequence information, which is information related to a specific species amino acid sequence that is an amino acid sequence related to a specific species.

  In addition, the non-self-recognizing partial sequence search unit 102d2 performs non-self-recognizing search score information, which is a score at the time of searching, by performing a search of the acquired partial sequence of the target sequence with respect to the specific species sequence information. It is a non-self-recognizing partial sequence search means to obtain.

  The search reference non-self-recognizing partial sequence predicting unit 102d3 is search reference non-self-recognizing partial sequence predicting means for predicting a non-self-recognizing partial sequence from the partial sequences based on the non-self-recognized search score information.

  Returning again to FIG. 2, the non-mutant partial sequence predicting unit 102e predicts a non-mutated partial sequence that is an amino acid sequence that is difficult to be mutated and is a partial sequence of the target sequence from the target sequence information. This is a partial sequence prediction means. Here, as shown in FIG. 7, the non-mutant partial sequence predicting unit 102e further includes a mutation probability predicting unit 102e1 and a probability reference non-mutant partial sequence predicting unit 102e2.

  FIG. 7 is a block diagram showing an example of the configuration of the non-mutated partial sequence predicting unit 102e of the system to which the present invention is applied, and conceptually shows only the portion related to the present invention in the configuration. . In FIG. 7, the mutation probability prediction unit 102e1 predicts a mutation probability based on a mutation prediction method for predicting a mutation probability that is a probability of causing mutation for each partial sequence of the target sequence. It is a mutation probability prediction means.

  The probability-based non-mutated partial sequence prediction unit 102e2 is a probability-based non-mutated partial sequence prediction unit that predicts a non-mutated partial sequence from the partial sequences based on the mutation probability.

  Returning again to FIG. 2, the vaccine candidate partial sequence predictor 102 f may perform the predicted non-cleaved partial sequence, the predicted MHC binding partial sequence, the predicted non-self-recognizing partial sequence, and / or the predicted non-mutation. This is a vaccine candidate partial sequence prediction means for predicting a vaccine candidate partial sequence that is an amino acid sequence effective as a vaccine based on the partial sequence. Here, as shown in FIG. 8, the vaccine candidate partial sequence predicting unit 102f is configured to further include a linear sum reference vaccine candidate partial sequence predicting unit 102f1.

  FIG. 8 is a block diagram showing an example of the configuration of the vaccine candidate partial sequence prediction unit 102f of the present system to which the present invention is applied, and conceptually shows only the portion related to the present invention in the configuration. In FIG. 8, the linear sum reference vaccine candidate partial sequence prediction unit 102f1 has at least one of cleavage site-containing sequence length partial sequence score information and cleavage site search score information calculated by the non-cut partial sequence prediction unit 102b, MHC binding At least one of MHC binding site-containing sequence length partial sequence score information, MHC binding site search score information, affinity information, structure evaluation index value information calculated by the partial sequence prediction unit 102c, non-self-recognized partial sequence prediction unit Linear that calculates the linear sum of the non-self-recognition search score information calculated in 102d and the mutation probability calculated in the non-mutated partial sequence prediction unit 102e, and predicts the vaccine candidate partial sequence based on the calculated linear sum It is a sum standard vaccine candidate partial sequence prediction means.

  Details of processing performed by these units will be described later.

System processing
Next, an example of processing of the system in the present embodiment configured as described above will be described in detail with reference to FIG.

Here, the main process performed in the vaccine candidate partial sequence prediction apparatus 100 will be described in detail with reference to FIG. 9 and the like.
FIG. 9 is a flowchart showing an example of main processing of the system according to the present embodiment.

  First, the vaccine candidate partial sequence prediction apparatus 100 acquires target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide, by the processing of the target sequence acquisition unit 102a, and a target sequence file 106a. (Step SA-1).

  Next, the vaccine candidate partial sequence prediction apparatus 100 uses the non-cleavable partial sequence prediction unit 102b to process the amino acid that is not cleaved by the proteolytic enzyme or proteosome present in the lysosome from the target sequence information acquired in Step SA-1. An uncut partial sequence (non-cut peptide) that is a partial sequence of the target sequence is predicted and stored in a predetermined storage area of the non-cut partial sequence file 106b8 (step SA-2).

  Here, in step SA-2, the non-cleavable partial sequence prediction unit 102b is information on a cleavage site-containing sequence that is an amino acid sequence including several residues before and after the enzyme cleavage site, which is a site cleaved by a proteolytic enzyme. The cleavage site-containing sequence information is stored, and the cleavage site-containing sequence amino acid appearance frequency information, which is information on the appearance frequency of the amino acid at the position corresponding to each amino acid residue in the stored cleavage site-containing sequence, is calculated and calculated. Based on the cleavage site-containing sequence amino acid appearance frequency information, the cleavage site-containing sequence score information is calculated, and based on the calculated cleavage site-containing sequence score information, the target sequence obtained in step SA-1 contains the cleavage site. Calculate the cleavage site containing sequence length partial sequence score information corresponding to each partial sequence divided into the length of the sequence, and include the calculated cleavage site An enzyme cleavage site may be determined based on the sequence length partial sequence score information, and a partial sequence cleaved at the enzyme cleavage site may be predicted as an uncut partial sequence (uncut peptide) (scoring based uncut partial sequence prediction) processing).

  Here, the score reference non-cutting partial sequence prediction processing performed in the non-cutting partial sequence prediction unit 102b will be described in detail with reference to FIG.

  FIG. 10 is a flowchart showing an example of the score reference non-cutting partial sequence prediction process of the system according to the present embodiment. In this embodiment, the non-cleavable partial sequence predicting unit 102b is an amino acid that includes several residues before and after the enzyme cleavage site that is a site cleaved by a proteolytic enzyme in advance by the processing of the cleavage site-containing sequence storage unit 102b1. It is assumed that the cleavage site-containing sequence information, which is information relating to the cleavage site-containing sequence that is the sequence, is stored in a predetermined storage area of the cleavage site-containing sequence file 106b1.

  First, the non-cleavable partial sequence predicting unit 102b obtains each amino acid residue in the cut site-containing sequence stored in the predetermined storage area of the cut site-containing sequence file 106b1 by the processing of the cut site-containing sequence amino acid appearance frequency calculating unit 102b2. Is calculated and stored in a predetermined storage area of the cleavage site-containing sequence amino acid appearance frequency file 106b2 (step SB-1).

  Next, the non-cleavable partial sequence prediction unit 102b obtains the cleavage site-containing sequence score information based on the cleavage site-containing sequence amino acid appearance frequency information calculated in step SB-1 by the processing of the cleavage site-containing sequence score calculation unit 102b3. Is calculated and stored in a predetermined storage area of the cleavage site-containing sequence score file 106b3 (step SB-2).

  Next, the non-cleaved partial sequence prediction unit 102b performs step SA-1 based on the cleavage site-containing sequence score information calculated in step SB-2 by the processing of the cleavage site-containing sequence length partial sequence score calculation unit 102b4. The cut site containing sequence length partial sequence score information corresponding to each partial sequence obtained by dividing the target sequence obtained by dividing the target sequence into the length of the cut site containing sequence is calculated, and a predetermined storage area of the cut site containing sequence length partial sequence file 106b4 (Step SB-3). In step SB-3, each partial sequence for which the cleavage site-containing sequence length partial sequence score information is calculated slides the target sequence obtained in step SA-1 by one amino acid residue from the beginning. However, it may be prepared by dividing the length of the cleavage site-containing sequence.

  Next, the non-cleavable partial sequence prediction unit 102b determines the enzyme cleavage site based on the cleavage site-containing sequence length partial sequence score information calculated in step SB-3 by the processing of the score reference non-cut partial sequence prediction unit 102b5. Then, the partial sequence cleaved at the enzyme cleavage site is predicted as a non-cleaved partial sequence (non-cleaved peptide), and stored in a predetermined storage area of the non-cleaved partial sequence file 106b8 (step SB-4). This completes the score reference non-cutting partial sequence prediction process.

  In step SA-2, the non-cleavable partial sequence predicting unit 102b stores the cleavage site sequence information that is information on the cleavage site sequence that is the amino acid sequence of the enzyme cleavage site that is the site cleaved by the proteolytic enzyme, Extracting a known cleavage site motif sequence from the stored cleavage site sequence information, and performing a motif search for the target sequence obtained in step SA-1 using the extracted cleavage site motif sequence To search for the enzyme cleavage site in the target sequence, obtain the cleavage site search score information that is the score at the time of the search, determine the enzyme cleavage site of the target sequence based on the obtained cleavage site search score information, and cleave the enzyme A partial sequence cleaved at a site may be predicted as a non-cut partial sequence (motif search reference non-cut partial sequence prediction process).

  Here, the motif search reference non-cut partial sequence prediction processing performed in the non-cut partial sequence prediction unit 102b will be described in detail with reference to FIG.

  FIG. 11 is a flowchart showing an example of the motif search reference non-cut partial sequence prediction process of the system according to the present embodiment. In this embodiment, the non-cleavable partial sequence prediction unit 102b relates to a cleavage site sequence that is an amino acid sequence of an enzyme cleavage site that is a site cleaved by a proteolytic enzyme in advance by the processing of the cleavage site sequence storage unit 102b6. It is assumed that the cut site sequence information, which is information, is stored in a predetermined storage area of the cut site sequence file 106b5.

  First, the non-cut partial sequence prediction unit 102b extracts a known cut site motif sequence from the cut site sequence information stored in a predetermined storage area of the cut site sequence file 106b5 by the processing of the cut site motif sequence extraction unit 102b7. And stored in a predetermined storage area of the cleavage site motif sequence file 106b6 (step SC-1).

  Next, the non-cut partial sequence prediction unit 102b uses the cut site motif sequence extracted in step SC-1 by the processing of the cut site motif search unit 102b8 to obtain the target sequence acquired in step SA-1. By executing a motif search on the target sequence, an enzyme cleavage site in the target sequence is searched, and a cleavage site search score information that is a score at the time of search is obtained and stored in a predetermined storage area of the cleavage site search score file 106b7 (step) SC-2).

  Next, the non-cleavable partial sequence prediction unit 102b determines the enzyme cleavage site of the target sequence based on the cut site search score information acquired in step SC-2 by the processing of the motif search reference non-cut partial sequence prediction unit 102b9. Then, the partial sequence cleaved at the enzyme cleavage site is predicted as a non-cleaved partial sequence and stored in a predetermined storage area of the non-cleaved partial sequence file 106b8 (step SC-3). This completes the motif search reference non-cut partial sequence prediction process.

  Returning to FIG. 9 again, the vaccine candidate partial sequence prediction apparatus 100 binds to a specific major histocompatibility antigen from the target sequence information acquired in step SA-1 by the processing of the MHC binding partial sequence prediction unit 102c. An MHC-binding partial sequence that is a possible amino acid sequence and is a partial sequence of the target sequence is predicted and stored in a predetermined storage area of the MHC-binding partial sequence file 106c17 (step SA-3).

  Here, in Step SA-3, the MHC binding partial sequence prediction unit 102c determines the type of a specific major histocompatibility antigen, and before and after the MHC binding site that is a site that binds to the determined major histocompatibility antigen. Stores MHC binding site-containing sequence information, which is information on an MHC binding site-containing sequence that is an amino acid sequence containing several residues, and the appearance of amino acids at positions corresponding to each amino acid residue in the stored MHC binding site-containing sequence MHC binding site-containing sequence amino acid appearance frequency information, which is information relating to the frequency, is calculated, MHC binding site-containing sequence amino acid score information is calculated based on the calculated MHC binding site-containing sequence amino acid appearance frequency information, and the calculated MHC binding Based on the site-containing sequence score information, each part distribution obtained by dividing the acquired target sequence into the length of the MHC binding site-containing sequence MHC binding site-containing sequence length partial sequence score information corresponding to is calculated, an MHC binding site-containing sequence length partial sequence score information is determined, an MHC binding site is determined, and the partial sequence including the MHC binding site is defined as MHC It may be predicted as a binding partial sequence (scoring standard MHC binding partial sequence prediction process).

  Here, the score reference MHC binding partial sequence prediction process performed by the MHC binding partial sequence prediction unit 102c will be described in detail with reference to FIG.

  FIG. 12 is a flowchart illustrating an example of the score reference MHC binding partial sequence prediction process of the system according to the present embodiment. In the present embodiment, the MHC binding partial sequence prediction unit 102c previously determines the type of a specific major histocompatibility antigen by the processing of the major histocompatibility antigen determination unit 102c1, and stores the MHC binding site-containing sequence storage unit. The MHC binding site-containing sequence information, which is information on the MHC binding site-containing sequence that is an amino acid sequence including several residues before and after the MHC binding site, which is a site that binds to the determined major histocompatibility antigen, is obtained by the processing of 102c2. It is assumed that it is stored in a predetermined storage area of the binding site-containing sequence file 106c1.

  First, the MHC binding site sequence predicting unit 102c, by the processing of the MHC binding site-containing sequence amino acid appearance frequency calculation unit 102c3, each MHC binding site-containing sequence stored in a predetermined storage area of the MHC binding site-containing sequence file 106c1. MHC binding site-containing sequence amino acid appearance frequency information, which is information relating to the appearance frequency of amino acids at positions corresponding to amino acid residues, is calculated and stored in a predetermined storage area of the MHC binding site-containing sequence amino acid appearance frequency file 106c2 (step SD). -1).

  Next, the MHC binding site containing sequence score calculation unit 102c4 performs the processing of the MHC binding site containing sequence score calculation unit 102c4 based on the MHC binding site containing sequence amino acid appearance frequency information calculated in step SD-1. Sequence score information is calculated and stored in a predetermined storage area of the MHC binding site-containing sequence score file 106c3 (step SD-2).

  Next, the MHC binding site-containing sequence predicting unit 102c performs step SA- based on the MHC binding site-containing sequence score information calculated in step SD-2 by the processing of the MHC binding site-containing sequence length partial sequence score calculation unit 102c5. MHC binding site-containing sequence length partial sequence score information corresponding to each partial sequence obtained by dividing the target sequence obtained in 1 into the length of the MHC binding site-containing sequence is calculated, and the MHC binding site-containing sequence length partial sequence file 106c4 In a predetermined storage area (step SD-3). In addition, each partial sequence for which MHC binding site-containing sequence length partial sequence score information is calculated includes the MHC binding site while sliding the target sequence obtained in step SA-1 by one amino acid residue from the beginning. It may be created by dividing the length of the array.

  Next, the MHC binding partial sequence predicting unit 102c determines the MHC binding site based on the MHC binding site-containing sequence length partial sequence score information calculated in step SD-3 by the processing of the score reference MHC binding partial sequence prediction unit 102c6. The partial sequence including the MHC binding site is predicted as an MHC binding partial sequence, and stored in a predetermined storage area of the MHC binding partial sequence file 106c17 (step SD-4). This completes the score reference MHC binding partial sequence prediction process.

  In step SA-3, the MHC binding partial sequence prediction unit 102c determines the type of a specific major histocompatibility antigen, and the amino acid sequence of the MHC binding site that is a site that binds to the determined major histocompatibility antigen. MHC binding site sequence information, which is information related to the MHC binding site sequence, is stored, a known MHC binding site motif sequence is extracted from the stored MHC binding site sequence information, and the extracted MHC binding site motif sequence is used Then, a motif search is performed on the target sequence acquired in step SA-1 to search for an MHC binding site in the target sequence, and MHC binding site search score information that is a score at the time of search is acquired and acquired. The MHC binding site is determined based on the obtained MHC binding site search score information, and the partial sequence including the MHC binding site is determined as MH. It may be predicted as a binding subsequences (Motif search criteria MHC binding subsequences prediction processing).

  Here, the motif search reference MHC binding partial sequence prediction process performed by the MHC binding partial sequence prediction unit 102c will be described in detail with reference to FIG.

  FIG. 13 is a flowchart showing an example of the motif search reference MHC binding partial sequence prediction process of the present system in the present embodiment. In the present embodiment, the MHC binding partial sequence prediction unit 102c previously determines the type of a specific major histocompatibility antigen by the processing of the major histocompatibility antigen determination unit 102c1, and the MHC binding site sequence storage unit 102c7. As a result of this processing, MHC binding site sequence information, which is information relating to the MHC binding site sequence that is the amino acid sequence of the MHC binding site that is the site that binds to the determined major histocompatibility antigen, is stored in the predetermined memory of the MHC binding site sequence file 106c5 It is assumed that it is stored in the area.

  First, the MHC binding partial sequence predicting unit 102c, by the processing of the MHC binding site motif sequence extracting unit 102c8, obtains a known MHC binding site from MHC binding site sequence information stored in a predetermined storage area of the MHC binding site sequence file 106c5. The motif sequence is extracted and stored in a predetermined storage area of the MHC binding site motif sequence file 106c6 (step SE-1).

  Next, the MHC binding partial sequence prediction unit 102c uses the MHC binding site motif sequence extracted in step SE-1 by the processing of the MHC binding site motif search unit 102c9, and the object acquired in step SA-1 A motif search is performed on the sequence to search for an MHC binding site in the target sequence, MHC binding site search score information, which is a score at the time of search, is acquired, and a predetermined storage area of the MHC binding site search score file 106c7 is obtained. Store (step SE-2).

  Next, the MHC binding partial sequence prediction unit 102c determines the MHC binding site based on the MHC binding site search score information acquired in step SE-2 by the processing of the motif search reference MHC binding partial sequence prediction unit 102c10. The partial sequence including the MHC binding site is predicted as an MHC binding partial sequence, and stored in a predetermined storage area of the MHC binding partial sequence file 106c17 (step SE-3). This completes the motif search reference MHC binding partial sequence prediction process.

  In Step SA-3, the MHC binding partial sequence prediction unit 102c determines the type of the specific major histocompatibility antigen, and relates to the major histocompatibility antigen sequence that is the amino acid sequence of the determined major histocompatibility antigen. The main histocompatibility antigen sequence information, which is information, is acquired, and the target sequence acquired in step SA-1 is divided into lengths corresponding to the determined type of main histocompatibility antigen, and the MHC length partial sequence And, based on each of the generated MHC length partial sequences and the obtained major histocompatibility antigen sequence, predict the complex three-dimensional structure information, and on the basis of the predicted complex three-dimensional structure information, Interacting amino acid information, which is information about the set of amino acids interacting between the sequence and the major histocompatibility antigen sequence, is determined and included in the determined interacting amino acid information. Affinity information, which is information about the affinity between amino acid pairs, is statistically calculated using the three-dimensional structure information of known proteins, and the sum of affinity information between all calculated amino acid pairs is calculated. The MHC binding partial sequence may be predicted by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on the calculated sum of the affinity information (affinity reference MHC binding partial sequence prediction). processing).

  Here, the affinity reference MHC binding partial sequence prediction process performed by the MHC binding partial sequence prediction unit 102c will be described in detail with reference to FIG.

  FIG. 14 is a flowchart showing an example of the affinity reference MHC binding partial sequence prediction process of the system according to the present embodiment.

  First, the MHC binding partial sequence prediction unit 102c determines the type of a specific major histocompatibility antigen by the processing of the major histocompatibility antigen determination unit 102c1 (step SF-1).

  Next, the MHC binding partial sequence prediction unit 102c is the main information that is information on the main histocompatibility antigen sequence that is the amino acid sequence of the main histocompatibility antigen determined in step SF-1 by the processing of the MHC sequence acquisition unit 102c11. The histocompatibility antigen sequence information is acquired and stored in a predetermined storage area of the MHC sequence file 106c8 (step SF-2).

  Next, the MHC binding partial sequence predicting unit 102c determines the type of major histocompatibility antigen determined in step SF-1 as the target sequence acquired in step SA-1 by the processing of the MHC long partial sequence creating unit 102c12. The MHC length partial sequence is created and stored in a predetermined storage area of the MHC length partial sequence file 106c9 (step SF-3). Here, the MHC long partial sequence creating unit 102c12 slides the target sequence acquired in step SA-1 by one amino acid residue from the beginning by the process of the slide dividing unit 102c13, in step SF-1. The MHC length subsequence may be generated by dividing into lengths corresponding to the determined major histocompatibility antigen types. The length corresponding to the type of major histocompatibility antigen may be, for example, 8 to 18 residues.

  Next, the MHC binding partial sequence predicting unit 102c performs the processing of the complex three-dimensional structure predicting unit 102c14, and the main tissue compatibility acquired in step SF-2 and each MHC long partial sequence created in step SF-3. Based on the antigen sequence, complex three-dimensional structure information is predicted and stored in a predetermined storage area of the predicted complex three-dimensional structure file 106c10 (step SF-4).

  Next, the MHC binding partial sequence prediction unit 102c performs the processing of the interaction amino acid determination unit 102c15, based on the complex three-dimensional structure information predicted in step SF-4, and the MHC long partial sequence and the major histocompatibility antigen sequence. Interacting amino acid information, which is information relating to a set of amino acids interacting with each other, is determined and stored in a predetermined storage area of the interacting amino acid file 106c11 (step SF-5).

  Next, the MHC binding partial sequence prediction unit 102c, by the processing of the affinity calculation unit 102c17, affinity information that is information on the affinity between the amino acid sets included in the interaction amino acid information determined in step SF-5, Statistical calculation is performed using the three-dimensional structure information of the known protein, and the information is stored in a predetermined storage area of the affinity file 106c12 (step SF-6).

  Here, in step SF-6, the MHC binding partial sequence prediction unit 102c binds to the major histocompatibility antigen determined in step SF-1 by the processing of the MHC binding amino acid residue distance value storage unit 102c16. MHC-binding amino acid residue distance value information, which is information relating to the distance value between each amino acid residue of the amino acid sequence and each amino acid residue of the major histocompatibility antigen sequence, is stored in the MHC-binding amino acid residue distance value file 106c13. The affinity calculation unit 102c17 stores the affinity information in the predetermined storage area, and the affinity information is stored in the predetermined storage area of the MHC-binding amino acid residue distance value file 106c13 by the processing of the distance value reference affinity calculation unit 102c18. Statistics based on distance information between amino acid residues and / or 3D structure information of known proteins Calculated using Tensharu may be stored in a predetermined memory region of the affinity file 106C12.

  Next, the MHC binding partial sequence prediction unit 102c calculates the sum of the affinity information among all the amino acid pairs calculated in step SF-6 by the processing of the affinity sum calculation unit 102c19 (step SF-7). .

  Next, the MHC binding partial sequence predicting unit 102c, based on the sum of the affinity information calculated in step SF-7 by the processing of the affinity reference MHC binding partial sequence predicting unit 102c20, is compatible with the main tissue compatibility with the MHC long partial sequence. By evaluating the affinity with the antigen, an MHC binding partial sequence is predicted and stored in a predetermined storage area of the MHC binding partial sequence file 106c17 (step SF-8). Thus, the affinity reference MHC binding partial sequence prediction process is completed.

  In Step SA-3, the MHC binding partial sequence prediction unit 102c determines the type of the specific major histocompatibility antigen, and acquires MHC three-dimensional structure information that is the determined three-dimensional structure of the major histocompatibility antigen. Based on the acquired MHC three-dimensional structure information and the partial sequence of the target sequence acquired in step SA-1, complex three-dimensional structure information of the major histocompatibility antigen and the partial sequence is created, and the composite In order to evaluate the three-dimensional structure corresponding to the three-dimensional structure information of a complex using quantum chemical calculation methods (for example, non-empirical molecular orbital method, semi-empirical molecular orbital method, MOZYME method) The structure evaluation index value information that is information about the value may be calculated, and the MHC binding partial sequence may be predicted from the partial sequence based on the calculated structure evaluation index value information (structure Value index reference MHC binding subsequences prediction processing).

  Here, the structure evaluation index reference MHC binding partial sequence prediction process performed in the MHC binding partial sequence prediction unit 102c will be described in detail with reference to FIG.

  FIG. 15 is a flowchart illustrating an example of the structure evaluation index reference MHC binding partial sequence prediction process of the system according to the present embodiment.

  First, the MHC binding partial sequence prediction unit 102c determines the type of a specific major histocompatibility antigen by the processing of the major histocompatibility antigen determination unit 102c1 (step SG-1).

  Next, the MHC binding partial sequence prediction unit 102c acquires MHC three-dimensional structure information that is the three-dimensional structure of the main histocompatibility antigen determined in step SG-1 by the processing of the MHC three-dimensional structure acquisition unit 102c21, and MHC three-dimensional structure information is obtained. The data is stored in a predetermined storage area of the structure file 106c14 (step SG-2).

  Next, the MHC binding partial sequence predicting unit 102c performs the processing of the complex three-dimensional structure creating unit 102c22 to obtain the MHC three-dimensional structure information acquired in Step SG-2 and the partial sequence of the target sequence acquired in Step SA-1. Based on the above, the three-dimensional structure information of the main histocompatibility antigen and the partial sequence is created and stored in a predetermined storage area of the created complex three-dimensional structure file 106c15 (step SG-3). The partial sequence may be created by dividing the target sequence obtained in step SA-1 while sliding it by one amino acid residue from the beginning.

  Next, the MHC binding partial sequence predicting unit 102c uses the quantum chemistry calculation method (for example, the ab initio molecular orbital method) in the complex three-dimensional structure information created in Step SG-3 by the process of the structure evaluation index calculating unit 102c23. , Semi-empirical molecular orbital method, MOZYME method, etc.) to calculate structure evaluation index value information, which is information related to index values for evaluating the three-dimensional structure corresponding to the three-dimensional structure information of the complex. The data is stored in a predetermined storage area 106c16 (step SG-4).

  Here, the structure evaluation index value information includes, for example, a semi-empirical molecular orbital calculation program “MOPAC2000” (product name) (Fujitsu Ltd. (company name)) that implements the MOZYME method, ab initio molecular orbital method. Orbital calculation program “Gaussian 98 Rev. A. 11.3” (product name) (Gaussian, Inc. (company name), Pittsburg PA. 2002) and “Gamess June 20 2002 R2” (product name) ( A value obtained as a result of energy calculation using Iowa State University, 2002) or the like may be used.

  Next, the MHC binding partial sequence predicting unit 102c performs the processing of the structure evaluation index reference MHC binding partial sequence prediction unit 102c24 based on the structure evaluation index value information calculated in step SG-4, from among the partial sequences. The binding partial sequence is predicted and stored in a predetermined storage area of the MHC binding partial sequence file 106c17 (step SG-5). Thus, the structure evaluation index reference MHC binding partial sequence prediction process is completed.

  Returning to FIG. 9 again, the vaccine candidate partial sequence prediction apparatus 100 is an amino acid sequence that is not recognized as self from the target sequence information acquired in step SA-1 by the processing of the non-self-recognizing partial sequence prediction unit 102d. The non-self-recognizing partial sequence that is a partial sequence of the target sequence is predicted and stored in a predetermined storage area of the non-self-recognizing partial sequence file 106d3 (step SA-4).

  Here, in step SA-4, the non-self-recognizing partial sequence predicting unit 102d stores specific biological species sequence information that is information on a specific biological species amino acid sequence that is an amino acid sequence related to a specific biological species (eg, human). Then, by executing a search for the partial sequence of the acquired target sequence with respect to the stored specific species sequence information, non-self-recognition search score information that is a score at the time of search is acquired, and Based on the self-recognition search score information, a non-self-recognized partial sequence may be predicted from the partial sequences (search reference non-self-recognized partial sequence prediction process). In step SA-4, a non-self-recognized partial sequence may be predicted using the technique described in Japanese Patent Application No. 2003-129554, which is a patent application filed by the present applicant.

  Here, the search reference non-self-recognition partial sequence prediction process performed by the non-self-recognition partial sequence prediction unit 102d will be described in detail with reference to FIG.

  FIG. 16 is a flowchart illustrating an example of the search reference non-self-recognizing partial sequence prediction process of the system according to the present embodiment. In the present embodiment, the non-self-recognizing partial sequence prediction unit 102d is previously processed by the specific biological species sequence storage unit 102d1, and the specific biological species amino acid sequence that is an amino acid sequence related to a specific biological species (eg, human) is preliminarily processed. It is assumed that specific species sequence information, which is information related to this, is stored in a predetermined storage area of the specific species sequence file 106d1.

  First, the non-self-recognizing partial sequence prediction unit 102d performs step SA on the specific biological species sequence information stored in the predetermined storage area of the specific biological species sequence file 106d1 by the processing of the non-self-recognizing partial sequence search unit 102d2. The non-self-recognition search score information, which is a score at the time of the search, is acquired by executing a search of the partial sequence of the target sequence acquired at -1, and stored in a predetermined storage area of the non-self-recognition search score file 106d2. (Step SH-1). The partial sequence may be created by dividing the target sequence obtained in step SA-1 while sliding it by one amino acid residue from the beginning.

  Next, the non-self-recognizing partial sequence predicting unit 102d is selected from the partial sequences based on the non-self-recognizing search score information acquired in step SH-1 by the processing of the search reference non-self-recognizing partial sequence predicting unit 102d3. A non-self-recognizing partial sequence is predicted and stored in a predetermined storage area of the non-self-recognizing partial sequence file 106d3 (step SH-2). This completes the search reference non-self-recognizing partial sequence prediction process.

  Returning to FIG. 9 again, the vaccine candidate partial sequence predicting apparatus 100 is an amino acid sequence that is difficult to be mutated from the target sequence information acquired in Step SA-1 by the processing of the non-mutated partial sequence predicting unit 102e. Thus, a non-mutated partial sequence that is a partial sequence of the target sequence is predicted and stored in a predetermined storage area of the non-mutated partial sequence file 106e2 (step SA-5).

  Here, in step SA-5, the non-mutated partial sequence predicting unit 102e predicts a mutation probability that is a probability of causing mutation for each partial sequence of the target sequence acquired in step SA-1. Based on a mutation prediction method (for example, refer to the patent publication “Patent No. 312957”), a mutation probability is predicted, and based on the predicted mutation probability, a partial sequence is selected. A non-mutated partial sequence may be predicted (probability-based non-mutated partial sequence prediction process).

  Here, the probability-based non-mutated partial sequence prediction process performed by the non-mutated partial sequence prediction unit 102e will be described in detail with reference to FIG.

  FIG. 17 is a flowchart illustrating an example of the probability criterion non-mutated partial sequence prediction process of the system according to the present embodiment.

  First, the non-mutated partial sequence predicting unit 102e is a mutation that is a probability of causing mutation for each partial sequence of the target sequence acquired in step SA-1 by the processing of the mutation probability predicting unit 102e1. Based on a mutation prediction method for predicting the probability (see, for example, the patent publication “Patent No. 312957”), the mutation probability is predicted and stored in a predetermined storage area of the mutation probability file 106e1. (Step SI-1). Here, the partial sequence may be created by dividing the target sequence obtained in Step SA-1 while sliding it by one amino acid residue from the beginning.

  Further, the technique described in the patent publication “Patent No. 312957” utilizes the fact that point mutation depends on a local partial sequence. Specifically, an error spectrum that is a set of mutation probabilities for each base in a DNA partial sequence is synthesized for a character string (a combination of four letters A, C, G, and T) to be predicted, By calculating the sum of the mutation probabilities, a base having a high sum is predicted to have a high probability of causing a mutation, thereby enabling prediction of gene mutation.

  Next, the non-mutated partial sequence predicting unit 102e performs non-mutation from the partial sequences based on the mutation probability predicted in step SI-1 by the processing of the probability-based non-mutated partial sequence predicting unit 102e3. The partial sequence is predicted and stored in a predetermined storage area of the non-mutated partial sequence file 106e2 (step SI-2). This completes the probability criterion non-mutated partial sequence prediction process.

  Returning to FIG. 9 again, the vaccine candidate partial sequence predicting apparatus 100 performs the process of the vaccine candidate partial sequence predicting unit 102f to perform the non-cut partial sequence predicted in step SA-2 and the MHC predicted in step SA-3. A vaccine that is an amino acid sequence effective as a vaccine based on the binding partial sequence, the non-self-recognizing partial sequence predicted in step SA-4, and / or the non-mutated partial sequence predicted in step SA-5 The candidate partial sequence is predicted and stored in a predetermined storage area of the vaccine candidate partial sequence file 106f (step SA-6).

  Here, in step SA-6, the vaccine candidate partial sequence prediction unit 102f is processed by the linear sum reference vaccine candidate partial sequence prediction unit 102f1, for example, the cleavage site-containing sequence length partial sequence calculated in step SA-2. At least one of score information and cleavage site search score information, MHC binding site-containing sequence length partial sequence score information calculated in step SA-3, MHC binding site search score information, sum of affinity information, structure evaluation index value At least one of the information, non-self-recognition search score information calculated in step SA-4, and a linear sum of mutation probabilities calculated in step SA-5 are calculated, and based on the calculated linear sum Vaccine candidate subsequences may be predicted. That is, the likelihood of peptide vaccine may be scored to take a linear sum, and a vaccine candidate partial sequence may be predicted based on the linear sum. Specifically, for example, a partial sequence having a high overall score may be predicted as a vaccine candidate partial sequence.

  As described above, in the present embodiment, the case where the processes of Step SA-2 to Step SA-5 are performed in parallel has been described as an example. For example, Step SA-2, Step SA-3, Step SA-4, Step SA By processing in series in the order of −5, candidates for partial sequences of the target sequence may be sequentially narrowed down, and finally the remaining partial sequences may be predicted as vaccine candidate partial sequences. Specifically, for example, among the partial sequences predicted in Step SA-2, for example, the lower order (for example, the set corresponding to the lower 80%) was excluded from the candidate amino acid sequences effective as a vaccine, and narrowed down. The partial sequence of the remaining set (for example, upper 20%) proceeds to step SA-3, and for example, the lower sequence (for example, the set corresponding to the lower 80%) of the partial sequence predicted in step SA-3 is vaccine. As a further sub-sequence of the remaining set (for example, the top 4%) that is finally narrowed down to step SA-4 and SA-5, the vaccine candidate sub-sequence is predicted. May be. In other words, by setting exclusion criteria (adoption criteria) to exclude (or adopt as peptide vaccine candidates) from peptide vaccine candidates at each step, a partial sequence that finally satisfies all exclusion criteria (adoption criteria) May be predicted as a vaccine candidate partial sequence.

  Thus, the main process ends.

[Other embodiments]
Although the embodiments of the present invention have been described so far, the present invention can be applied to various different embodiments in addition to the above-described embodiments within the scope of the technical idea described in the claims. May be implemented.

  For example, the vaccine candidate partial sequence prediction device 100 performs processing in response to a request from a client terminal configured with a separate housing from the vaccine candidate partial sequence prediction device 100, and returns the processing result to the client terminal. You may comprise.

  In addition, among the processes described in the embodiment, all or part of the processes described as being performed automatically can be performed manually, or all of the processes described as being performed manually are performed. Alternatively, a part can be automatically performed by a known method.

  In addition, the processing procedures, control procedures, specific names, information including parameters such as various registration data and search conditions, screen examples, and database configurations shown in the above documents and drawings, unless otherwise specified. It can be changed arbitrarily.

  Moreover, regarding the vaccine candidate partial sequence predicting apparatus 100, each illustrated component is functionally conceptual and does not necessarily need to be physically configured as illustrated.

  For example, each part of the vaccine candidate partial sequence predicting apparatus 100 or a processing function included in each apparatus, in particular, each processing function performed by the control unit 102 is entirely or arbitrarily part of the CPU (Central Processing Unit) and the relevant part. It can be realized by a program interpreted and executed by the CPU, or can be realized as hardware by wired logic. The program is recorded on a recording medium to be described later, and is mechanically read by the vaccine candidate partial sequence prediction apparatus 100 as necessary.

  That is, in the storage unit 106 such as a ROM or an HD, a computer program for giving instructions to the CPU and performing various processes in cooperation with an OS (Operating System) is recorded. The computer program is executed by being loaded into a RAM or the like, and constitutes the control unit 102 in cooperation with the CPU. In addition, this computer program may be recorded in an application program server connected to the vaccine candidate partial sequence prediction apparatus 100 via an arbitrary network 300, and may be downloaded in whole or in part as necessary. Is also possible.

  The program according to the present invention can also be stored in a computer-readable recording medium. Here, the “recording medium” is an arbitrary “portable physical medium” such as a flexible disk, a magneto-optical disk, a ROM, an EPROM, an EEPROM, a CD-ROM, an MO, and a DVD, and is incorporated in various computer systems. Program in a short time, such as a communication line or carrier wave when transmitting a program via any “fixed physical medium” such as ROM, RAM, HD, or a network such as LAN, WAN, or the Internet The “communication medium” that holds

  The “program” is a data processing method described in an arbitrary language or description method, and may be in any format such as source code or binary code. The “program” is not necessarily limited to a single configuration, but is distributed in the form of a plurality of modules and libraries, or in cooperation with a separate program represented by an OS (Operating System). Including those that achieve the function. Note that a well-known configuration and procedure can be used for a specific configuration for reading a recording medium, a reading procedure, an installation procedure after reading, and the like in each device described in the embodiment.

  Various files and the like (target sequence file 106a to vaccine candidate partial sequence file 106f) stored in the storage unit 106 are storage means such as a memory device such as RAM and ROM, a fixed disk device such as a hard disk, a flexible disk, and an optical disk. Yes, it stores various programs, tables, files, databases, web page files, etc. used for various processes and website provision.

  The vaccine candidate partial sequence prediction apparatus 100 connects a peripheral device such as a printer, a monitor, or an image scanner to an information processing apparatus such as an information processing terminal such as a known personal computer or workstation, and the present invention is applied to the information processing apparatus. You may implement | achieve by mounting the software (a program, data, etc. are included) which implement | achieve this method.

  Furthermore, the specific form of distribution / integration of the vaccine candidate partial sequence predicting apparatus 100 is not limited to that shown in the figure, and all or a part thereof may be functionally or physically in arbitrary units according to various loads. It can be configured to be distributed and integrated. For example, each database may be independently configured as an independent database device, and a part of the processing may be realized by using CGI (Common Gateway Interface).

  The network 300 has a function of connecting the vaccine candidate partial sequence prediction device 100 and the external system 200 to each other. For example, the Internet, an intranet, a LAN (including both wired / wireless), VAN, PC communication network, public telephone network (including both analog / digital), dedicated line network (including both analog / digital), CATV network, IMT2000 system, GSM system or PDC / PDC-P system Or a mobile phone switching network / portable packet switching network, a wireless paging network, a local wireless network such as Bluetooth, a PHS network, a satellite communication network such as CS, BS, or ISDB. That is, this system can transmit and receive various data via any network regardless of wired or wireless.

  An example (Example 1) using the vaccine candidate partial sequence prediction apparatus 100 in the above-described embodiment will be described with reference to FIGS. FIG. 18 is a principle configuration diagram showing the basic principle of the first embodiment.

  First, the amino acid sequence of the antigen protein is acquired by the processing of the target sequence acquisition unit 102a in the embodiment described above.

  Next, a candidate for a cleaved peptide fragment is predicted from the obtained amino acid sequence of the antigen protein by the process performed by the non-cleaved partial sequence prediction unit 102b in the above-described embodiment (SJ-1: lysosomal enzyme or proteosome cleavage pattern analysis). .

  Next, the major histocompatibility antigen determined by the processing performed in the MHC binding partial sequence prediction unit 102c (major histocompatibility antigen determination unit 102c1 to motif search reference MHC binding partial sequence prediction unit 102c10) in the above-described embodiment. MHC-binding peptide fragment candidates are predicted for the types (step SJ-2: MHC binding prediction (sequence)).

  Next, a common peptide fragment candidate that is a peptide fragment common to the cleaved peptide fragment candidate and the MHC binding peptide fragment candidate is extracted by the processing of the control unit 102 in the above-described embodiment (step SJ-3: common candidate extraction).

  Next, the processing performed in the MHC binding partial sequence prediction unit 102c (major histocompatibility antigen determination unit 102c1, MHC sequence acquisition unit 102c11 to structure evaluation index reference MHC binding partial sequence prediction unit 102c24) in the above-described embodiment is common. The peptide fragment candidates are further narrowed down (step SJ-4: MHC binding prediction (structure)).

  Next, the common peptide fragment candidates narrowed down in step SJ-4 are further narrowed down by the process performed by the non-self-recognizing partial sequence prediction unit 102d in the above-described embodiment (step SJ-5: antigenicity evaluation).

  Next, by further narrowing down the common peptide fragment candidates narrowed down in step SJ-5 by the processing performed in the non-mutated partial sequence predicting unit 102e in the above-described embodiment, the vaccine candidate partial sequence in the above-described embodiment. Is extracted (step SJ-6: mutation evaluation).

  Next, a process performed by the vaccine candidate partial sequence prediction apparatus 100 according to the first embodiment will be described with reference to FIGS. 19 to 36. FIG. 19 is a flowchart illustrating main processing performed by the vaccine candidate partial sequence prediction apparatus 100 according to the first embodiment.

  That is, the vaccine candidate partial sequence prediction apparatus 100 acquires the type of antigen protein sequence and major histocompatibility antigen (MHC), and predicts the cleavage pattern of the lysosomal enzyme or proteosome in the antigen protein sequence (step SK- 1: prediction of lysosomal enzyme or proteosome cleavage pattern).

  Here, the specific processing in step SK-1 is performed with reference to the data shown in FIGS. 22 to 25 based on the flowchart shown in FIG. 20 or FIG.

  Next, the vaccine candidate partial sequence predicting apparatus 100 predicts based on the sequence whether or not the fragment peptide that is the antigen protein sequence cleaved with the cleavage pattern predicted in Step SK-1 binds to MHC (Step SK−). 2: MHC binding prediction (sequence)).

  Here, the specific processing in step SK-2 is performed with reference to each data shown in FIG. 28 and FIG. 29 based on the flowchart shown in FIG.

  Next, the vaccine candidate partial sequence predicting apparatus 100 determines whether or not the MHC binding peptide candidate, which is a fragment peptide predicted to bind to MHC based on the sequence in step SK-2, further binds to MHC based on the structure. (Step SK-3: MHC binding prediction (structure)).

  Here, the specific processing in step SK-3 is performed with reference to each data shown in FIG. 32 and FIG. 33 based on the flowchart shown in FIG.

  Next, the vaccine candidate partial sequence prediction apparatus 100 evaluates the antigenicity of the MHC-binding peptide candidate predicted to bind to MHC based on the structure in step SK-3 (step SK-4: antigenicity evaluation).

  Here, the specific processing in step SK-4 is performed with reference to the data shown in FIG. 36 based on the flowchart shown in FIG.

  Next, the vaccine candidate partial sequence prediction apparatus 100 predicts the ease of introduction of mutations for peptide vaccine candidates that are MHC-binding peptide candidates evaluated as having no antigenicity in step SK-4 (step SK-5). : Mutation prediction).

  Here, the specific processing in step SK-5 is performed based on the flowchart shown in FIG.

  Next, the vaccine candidate partial sequence prediction apparatus 100 extracts the peptide vaccine candidate predicted to be difficult to be mutated in Step SK-5 as a peptide vaccine candidate (vaccine candidate) resistant to mutation.

  The peptide fragments extracted by the above processing are shown in FIGS.

  FIG. 37 is a diagram showing a result of predicting a peptide fragment for HLA A * 0201 of Envelop polyprotein GP160 of Human immunofluidity virus type 1 (HXB2 isolate).

  The CTL epitope for HLA A * 0201 of Envelop polyprotein GP160 of Human immunodevelopment virus type 1 (HXB2 isolate) is “KLTLPLCVSL”, “RIQRGGPRAVVTI”, “SLLNATAI”. According to the present invention, the score of “KLTPLCVS” is in position 13 (in 849 peptides), “RIQRGGR” is in position 8 (in 849 peptides), “SLLNATAI” is in position 45 (in 849 peptides) A high score was obtained for the peptide to be bound. It has been demonstrated that “KLTPLCVS” having a score of 13th actually activates CTL.

  FIG. 38 is a diagram showing the results of predicting peptide fragments for HLA A * 0201 of the negative factor of Human immunovirtuality virus type 1 (HXB2 isolate).

  The CTL epitopes for negative factor HLA A * 0201 in Human immunodevelopment virus type 1 (HXB2 isolate) are known as “PLTFGWCYKLV”, “VLEWRFDSRL”, “AFHHVAREL”, etc. According to the present invention, the score of “LTFGWCYK” is 12th (in 199 peptides), “VLEWRFDS” is in 32nd position (in 199 peptides), “RLAFHHVA” is 18th (in 199 peptides) A high score was obtained for the peptide to be bound. It has been demonstrated that “LTFGGWCYK” having a score of 12th actually activates CTL.

  As described above, according to Example 1, it became possible to efficiently predict the CLT epitope.

  An example (Example 2) using the vaccine candidate partial sequence prediction apparatus 100 in the above-described embodiment will be described with reference to FIGS. 39 to 43. FIG. 39 is a principle configuration diagram showing the basic principle of the second embodiment.

  First, the process performed by the uncut partial sequence prediction unit 102b in the above-described embodiment divides the amino acid sequence of the protein into fragment peptides, predicts the cleavage pattern for the fragment peptides, and selects the lower 20% fragment peptides. It excludes from a candidate (step SU-1: cutting pattern prediction).

  Next, the processing performed in the MHC binding partial sequence prediction unit 102c (major histocompatibility antigen determination unit 102c1 to motif search reference MHC binding partial sequence prediction unit 102c10) in the above-described embodiment is not excluded in step SU-1. Based on the sequence, the fragment peptide is predicted to bind to MHC, and the lower 80% fragment peptide is excluded from the candidates (step SU-2: MHC binding prediction (sequence)).

  Next, a process performed by the MHC binding partial sequence prediction unit 102c (major histocompatibility antigen determination unit 102c1, MHC sequence acquisition unit 102c11 to structure evaluation index reference MHC binding partial sequence prediction unit 102c24) in the above-described embodiment is performed. Based on the structure, it is predicted whether the fragment peptides that have not been excluded in SU-2 will bind to MHC, and sorted and output from those with good scores (step SU-3: MHC binding prediction (structure)). Note that the processing in step SU-3 is performed with reference to the data shown in FIGS.

  The fragment peptide extracted by the above processing is shown in FIG.

  FIG. 43 is a diagram showing a result of predicting a fragment peptide for HLA A2 of Envelop polyprotein GP160 of Human immunofidelity virus type 1 (HXB2 isolate).

  “GDPEIVTHSF” is known as a CLT epitope for HLA A2 of Envelop Polyprotein GP160 of Human immunodevelopment virus type 1 (HXB2 isolate). According to the present invention, the score of “GDPEIVTHS” was as high as 4th place (in 848 peptides). It has been confirmed by experiments that the fragment peptide at position 4 actually binds to MCH.

  As described above, according to Example 2, it has become possible to efficiently and quickly predict a fragment peptide that binds to MHC.

  As described above, the vaccine candidate partial sequence prediction apparatus, the vaccine candidate partial sequence prediction method, the program, and the recording medium according to the present invention are amino acids capable of activating T cells from the amino acid sequence of a protein or physiologically active polypeptide. By predicting the sequence (peptide sequence), it is possible to predict the amino acid sequence to be a vaccine with high accuracy, and it can be widely implemented in many industrial fields, especially in the fields of pharmaceuticals, medical care, life science industries, etc. Can be very useful.

  In addition, the MHC binding partial sequence prediction apparatus, MHC binding partial sequence prediction method, program and recording medium according to the present invention can bind to a specific major histocompatibility antigen from the amino acid sequence of a protein or bioactive polypeptide. Amino acid sequences (peptide sequences) can be predicted with high accuracy, and can be widely implemented in many industrial fields, particularly in the fields of pharmaceuticals, medical care, life science industries, etc., and are extremely useful.

It is a principle block diagram which shows the basic principle of this invention. It is a block diagram which shows an example of a structure of this system with which this invention is applied. It is a figure which shows an example of the information stored in the memory | storage part 106 of this system with which this invention is applied. It is a block diagram which shows an example of a structure of the non-cut | disconnecting partial arrangement | sequence prediction part 102b of this system with which this invention is applied. It is a block diagram which shows an example of a structure of the MHC coupling | bonding partial sequence estimation part 102c of this system with which this invention is applied. It is a block diagram which shows an example of a structure of the non-self recognition partial arrangement | sequence prediction part 102d of this system with which this invention is applied. It is a block diagram which shows an example of a structure of the non-mutation partial sequence estimation part 102e of this system with which this invention is applied. It is a block diagram which shows an example of a structure of the vaccine candidate partial arrangement | sequence prediction part 102f of this system with which this invention is applied. It is a flowchart which shows an example of the main process of this system in this embodiment. It is a flowchart which shows an example of the score reference | standard non-cut | disconnecting partial arrangement | sequence prediction process of this system in this embodiment. It is a flowchart which shows an example of the motif search reference | standard non-cut | disconnecting partial arrangement | sequence prediction process of this system in this embodiment. It is a flowchart which shows an example of the score reference | standard MHC coupling | bonding partial arrangement | sequence prediction process of this system in this embodiment. It is a flowchart which shows an example of the motif search reference | standard MHC binding partial sequence prediction process of this system in this embodiment. It is a flowchart which shows an example of the affinity reference | standard MHC binding partial sequence prediction process of this system in this embodiment. It is a flowchart which shows an example of the structure evaluation index reference | standard MHC coupling | bonding partial sequence prediction process of this system in this embodiment. It is a flowchart which shows an example of the search reference | standard non-self recognition partial arrangement | sequence prediction process of this system in this embodiment. It is a flowchart which shows an example of the probability reference | standard non-mutation partial arrangement | sequence prediction process of this system in this embodiment. It is a principle block diagram which shows the basic principle of the present Example 1. FIG. It is a flowchart of the main process performed in the vaccine candidate partial arrangement | sequence prediction apparatus 100 in the present Example 1. FIG. It is a flowchart of the cutting | disconnection pattern prediction process performed with the vaccine candidate partial arrangement | sequence prediction apparatus 100 in the present Example 1. FIG. It is a flowchart which shows the cutting pattern prediction process performed with the vaccine candidate partial arrangement | sequence prediction apparatus 100 in the present Example 1. FIG. It is a figure which shows the cutting site amino acid sequence referred in the cutting pattern prediction process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. FIG. It is a figure which shows the cutting site amino acid frequency referred in the cutting pattern prediction process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. FIG. It is a figure which shows the cutting | disconnection site | part amino acid score referred by the cutting | disconnection pattern prediction process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. FIG. It is a figure which shows the cutting site motif referred in the cutting pattern prediction process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. FIG. It is a flowchart of the MHC binding prediction (sequence) process performed in the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. It is a flowchart of the MHC binding prediction (sequence) process performed in the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. It is a figure which shows the MHC binding peptide referred by the MHC binding prediction (sequence) process performed in the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. It is a figure which shows the MHC binding peptide amino acid frequency referred in the MHC binding prediction (sequence) process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. It is a flowchart of the MHC coupling | bonding prediction (structure) process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. FIG. It is a flowchart of the MHC coupling | bonding prediction (structure) process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. FIG. It is a figure which shows the distance value between MHC binding peptide amino acids referred in the MHC binding prediction (structure) process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. It is a figure which shows the MHC / peptide complex crystal structure data referred by the MHC binding prediction (structure) process performed with the vaccine candidate partial arrangement | sequence prediction apparatus 100 in the present Example 1. FIG. It is a flowchart of the antigenicity evaluation process performed in the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. It is a flowchart of the mutation prediction process performed in the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. It is a figure which shows the known human amino acid sequence referred by the antigenicity evaluation process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 1. FIG. It is a figure which shows the result of having estimated the peptide fragment with respect to HLA A * 0201 of Envelop polyprotein GP160 of Human immunofidelity virus type 1 (HXB2 isolate). It is a figure which shows the result of having predicted the peptide fragment with respect to HLA A * 0201 of Negative factor of Human immunodevelopment virus type 1 (HXB2 isolate). It is a principle block diagram which shows the basic principle of the present Example 2. It is a figure which shows the complex structure and complex distance information which are referred by the MHC coupling | bonding prediction (structure) process performed with the vaccine candidate partial arrangement | sequence prediction apparatus 100 in the present Example 2. FIG. It is a figure which shows the interaction amino acid group referred in the MHC binding prediction (structure) process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 2. FIG. It is a figure which shows the sum total of the affinity of the interaction amino acid group referred in the MHC binding prediction (structure) process performed with the vaccine candidate partial sequence prediction apparatus 100 in the present Example 2. It is a figure which shows the result of having estimated the fragment peptide with respect to HLA A2 of Envelop polyprotein GP160 of Human immunodevelopment virus type 1 (HXB2 isolate).

Explanation of symbols

100 Vaccine Candidate Partial Sequence Prediction Device 102 Control Unit
102a Target sequence acquisition unit
102b Uncut partial sequence predictor
102b1 cleavage site containing sequence storage section
102b2 cleavage site-containing sequence amino acid appearance frequency calculation unit
102b3 cleavage site-containing sequence score calculation unit
102b4 cleavage site-containing sequence length partial sequence score calculation unit
102b5 Score criterion non-cutting partial sequence prediction unit
102b6 cutting site sequence storage
102b7 cleavage site motif sequence extraction unit
102b8 cleavage site motif search part
102b9 Motif search reference uncut partial sequence predictor
102c MHC binding partial sequence prediction unit (MHC binding partial sequence prediction device)
102c1 Major histocompatibility antigen determination part
102c2 MHC binding site-containing sequence storage
102c3 MHC binding site-containing sequence amino acid appearance frequency calculation unit
102c4 MHC binding site-containing sequence score calculation unit
102c5 MHC binding site-containing sequence length partial sequence score calculation unit
102c6 Score criteria MHC binding subsequence prediction unit
102c7 MHC binding site sequence storage
102c8 MHC binding site motif sequence extractor
102c9 MHC binding site motif search part
102c10 Motif search reference MHC binding partial sequence prediction unit
102c11 MHC sequence acquisition unit
102c12 MHC long partial sequence generator
102c13 slide dividing unit
102c14 Complex three-dimensional structure prediction unit
102c15 interacting amino acid determinant
102c16 MHC-binding amino acid residue distance value storage
102c17 affinity calculator
102c18 Distance value reference affinity calculator
102c19 Total affinity calculator
102c20 Affinity reference MHC binding partial sequence predictor
102c21 MHC three-dimensional structure acquisition unit
102c22 composite three-dimensional structure creation unit
102c23 Structure evaluation index calculation unit
102c24 Structure Evaluation Index Criteria MHC Binding Partial Sequence Prediction Unit
102d Non-self-recognizing partial sequence prediction unit
102d1 specific species array storage
102d2 Non-self-recognizing partial sequence search unit
102d3 Search criterion non-self-recognizing partial sequence prediction unit
102e Non-mutated partial sequence prediction unit
102e1 mutation probability prediction unit
102e2 Probability-based non-mutated partial sequence predictor
102f Vaccine candidate partial sequence prediction unit
102f1 linear sum reference vaccine candidate partial sequence prediction unit 104 communication control interface unit 106 storage unit
106a Target sequence file
106b1 cleavage site-containing sequence file
106b2 Cleavage site-containing sequence amino acid appearance frequency file
106b3 cleavage site-containing sequence score file
106b4 Cleavage site-containing sequence length partial sequence file
106b5 cleavage site sequence file
106b6 cleavage site motif sequence file
106b7 Cut site search score file
106b8 Uncut partial sequence file
106c1 MHC binding site-containing sequence file
106c2 MHC binding site-containing sequence amino acid frequency file
106c3 MHC binding site-containing sequence score file
106c4 MHC binding site-containing sequence length partial sequence file
106c5 MHC binding site sequence file
106c6 MHC binding site motif sequence file
106c7 MHC binding site search score file
106c8 MHC sequence file
106c9 MHC long partial sequence file
106c10 Prediction complex 3D structure file
106c11 interacting amino acid file
106c12 affinity file
106c13 MHC binding amino acid residue distance value file
106c14 MHC 3D structure file
106c15 Creation complex 3D structure file
106c16 Structure evaluation index value file
106c17 MHC binding partial sequence file
106d1 Specific species sequence file
106d2 Non-self-recognition search score file
106d3 Non-self-recognizing partial sequence file
106e1 mutation probability file
106e2 Non-mutated partial sequence file
106f Vaccine candidate partial sequence file 108 Input / output control interface unit 112 Input device 114 Output device 200 External system 300 Network

Claims (47)

A target sequence acquisition means for acquiring target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide;
Based on the target sequence information acquired by the target sequence acquisition means, the amino acid sequence that is not cleaved by a proteolytic enzyme or proteosome present in lysosomes, and predicts an uncut partial sequence that is a partial sequence of the target sequence An uncut partial sequence predicting means;
Based on the target sequence information acquired by the target sequence acquisition means, the amino acid sequence capable of binding to a specific major histocompatibility antigen, and an MHC binding partial sequence that is a partial sequence of the target sequence is predicted MHC binding partial sequence prediction means;
Non-self-recognizing partial sequence predicting means for predicting a non-self-recognizing partial sequence that is the amino acid sequence that is not recognized as self from the target sequence information acquired by the target sequence acquiring means and that is a partial sequence of the target sequence; ,
Non-mutated partial sequence predicting means for predicting a non-mutated partial sequence that is the amino acid sequence that is difficult to be mutated and is a partial sequence of the target sequence from the target sequence information acquired by the target sequence acquiring means When,
The non-cleaved partial sequence predicted by the non-cleaved partial sequence predicting means, the MHC-binding partial sequence predicted by the MHC-binding partial sequence predicting means, and the non-self-recognized predicted by the non-self-recognized partial sequence predicting means Vaccine candidate partial sequence prediction for predicting a vaccine candidate partial sequence that is the amino acid sequence effective as a vaccine based on the partial sequence and / or the non-mutated partial sequence predicted by the non-mutated partial sequence predicting means Means,
A vaccine candidate partial sequence predicting apparatus comprising: The non-cutting partial sequence predicting means includes:
A cleavage site-containing sequence storage means for storing cleavage site-containing sequence information, which is information relating to the cleavage site-containing sequence, which is the amino acid sequence including several residues before and after the enzyme cleavage site, which is a site cleaved by the proteolytic enzyme;
A cleavage site-containing sequence for calculating cleavage site-containing sequence amino acid appearance frequency information, which is information relating to the appearance frequency of amino acids at positions corresponding to each amino acid residue in the cleavage site-containing sequence stored by the cleavage site-containing sequence storage means Amino acid appearance frequency calculating means,
Based on the cleavage site-containing sequence amino acid appearance frequency information calculated by the cleavage site-containing sequence amino acid appearance frequency calculation unit, a cleavage site-containing sequence score calculation unit that calculates cleavage site-containing sequence score information;
Each partial sequence obtained by dividing the target sequence obtained by the target sequence obtaining unit into the length of the cleavage site-containing sequence based on the cleavage site-containing sequence score information calculated by the cleavage site-containing sequence score calculating unit A cleavage site-containing sequence length partial sequence score calculating means for calculating a cleavage site-containing sequence length partial sequence score information corresponding to:
Determine the enzyme cleavage site based on the cleavage site-containing sequence length partial sequence score information calculated by the cleavage site-containing sequence length partial sequence score calculation means, and the partial sequence cleaved at the enzyme cleavage site is not cleaved A score-based non-cutting partial sequence predicting means for predicting as a partial sequence,
The vaccine candidate partial sequence prediction apparatus according to claim 1, further comprising: The non-cutting partial sequence predicting means includes:
A cleavage site sequence storage means for storing cleavage site sequence information that is information relating to the cleavage site sequence that is the amino acid sequence of the enzyme cleavage site that is a site cleaved by the proteolytic enzyme;
From the cleavage site sequence information stored by the cleavage site sequence storage means, a cleavage site motif sequence extraction means for extracting a known cleavage site motif sequence;
The enzyme cleavage site in the target sequence by performing a motif search on the target sequence acquired by the target sequence acquisition unit using the cleavage site motif sequence extracted by the cleavage site motif sequence extraction unit Cutting site motif search means for acquiring cutting site search score information that is a score at the time of searching,
The enzyme cleavage site of the target sequence is determined based on the cleavage site search score information acquired by the cleavage site motif search means, and a partial sequence cleaved at the enzyme cleavage site is predicted as the non-cleavable partial sequence Motif search reference uncut partial sequence predicting means;
The vaccine candidate partial sequence prediction apparatus according to claim 1, further comprising: The MHC binding partial sequence predicting means comprises:
A major histocompatibility determining means for determining the type of said particular major histocompatibility antigen;
MHC binding which is information on the MHC binding site-containing sequence which is the amino acid sequence including several residues before and after the MHC binding site which is the site binding to the major histocompatibility antigen determined by the major histocompatibility determining means MHC binding site-containing sequence storage means for storing site-containing sequence information;
MHC for calculating MHC binding site-containing sequence amino acid appearance frequency information, which is information regarding the appearance frequency of amino acids at positions corresponding to each amino acid residue in the MHC binding site-containing sequence stored by the MHC binding site-containing sequence storage means A binding site-containing sequence amino acid appearance frequency calculating means;
MHC binding site-containing sequence score calculation means for calculating MHC binding site-containing sequence amino acid score information based on the MHC binding site-containing sequence amino acid appearance frequency information calculated by the MHC binding site-containing sequence amino acid appearance frequency calculation means;
Based on the MHC binding site-containing sequence score information calculated by the MHC binding site-containing sequence score calculation means, the target sequence acquired by the target sequence acquisition means is divided into the length of the MHC binding site-containing sequence. MHC binding site-containing sequence length partial sequence score calculating means for calculating MHC binding site-containing sequence length partial sequence score information corresponding to each partial sequence;
The MHC binding site-containing sequence length partial sequence score calculation means calculates the MHC binding site based on the MHC binding site-containing sequence length partial sequence score information, and the partial sequence including the MHC binding site is determined as the MHC binding site. A score-based MHC binding partial sequence predicting means for predicting as a binding partial sequence;
The vaccine candidate partial sequence prediction apparatus according to any one of claims 1 to 3, further comprising: The MHC binding partial sequence predicting means comprises:
A major histocompatibility determining means for determining the type of said particular major histocompatibility antigen;
An MHC that stores MHC binding site sequence information that is information on the MHC binding site sequence that is the amino acid sequence of the MHC binding site that is the site that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determining means Binding site sequence storage means;
MHC binding site motif sequence extraction means for extracting a known MHC binding site motif sequence from the MHC binding site sequence information stored by the MHC binding site sequence storage means;
Using the MHC binding site motif sequence extracted by the MHC binding site motif sequence extraction means, a motif search is performed on the target sequence acquired by the target sequence acquisition unit, whereby the MHC in the target sequence is obtained. MHC binding site motif search means for searching for a binding site and obtaining MHC binding site search score information which is a score at the time of search;
Motif search criteria for determining the MHC binding site based on the MHC binding site search score information obtained by the MHC binding site motif search means and predicting the partial sequence including the MHC binding site as the MHC binding partial sequence MHC binding partial sequence prediction means;
The vaccine candidate partial sequence prediction apparatus according to any one of claims 1 to 3, further comprising: The MHC binding partial sequence predicting means comprises:
A major histocompatibility determining means for determining the type of said particular major histocompatibility antigen;
MHC sequence acquisition means for acquiring main histocompatibility antigen sequence information, which is information on the main histocompatibility antigen sequence that is the amino acid sequence of the main histocompatibility antigen determined by the main histocompatibility antigen determination means;
Dividing the target sequence obtained by the target sequence obtaining means into lengths corresponding to the types of the major histocompatibility antigens determined by the major histocompatibility antigen determining means, and creating an MHC long partial sequence MHC length partial sequence creating means
Complex three-dimensional structure prediction for predicting complex three-dimensional structure information based on each MHC long partial sequence created by the MHC long partial sequence creating means and the major histocompatibility antigen sequence obtained by the MHC sequence obtaining means Means,
Based on the complex three-dimensional structure information predicted by the complex three-dimensional structure prediction means, information on the set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence. An interacting amino acid determining means for determining certain interacting amino acid information;
Affinity information, which is information related to the affinity between the amino acid pairs included in the interacting amino acid information determined by the interacting amino acid determining means, is statistically calculated using the three-dimensional structure information of a known protein. An affinity calculation means;
An affinity sum calculation means for calculating the sum of the affinity information among all the amino acid pairs calculated by the affinity calculation means;
Affinity for predicting the MHC binding partial sequence by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on the total of the affinity information calculated by the affinity total calculation means A reference MHC binding subsequence prediction means;
The vaccine candidate partial sequence prediction apparatus according to any one of claims 1 to 3, further comprising: The MHC long partial sequence creating means includes:
The target sequence acquired by the target sequence acquisition means is divided into the length corresponding to the type of the major histocompatibility antigen while sliding by one amino acid residue from the beginning, and the MHC long partial sequence is Slide dividing means to create,
The vaccine candidate partial sequence prediction apparatus according to claim 6, further comprising: The length corresponding to the type of major histocompatibility antigen is 8-18 residues,
The vaccine candidate partial sequence prediction apparatus according to claim 6 or 7, wherein The MHC binding partial sequence predicting means comprises:
Information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determining means and each amino acid residue of the major histocompatibility antigen sequence MHC binding amino acid residue distance value storage means for storing MHC binding amino acid residue distance value information,
Further comprising
The affinity calculation means is:
Statistical potential using the MHC binding amino acid residue distance value information stored in the MHC binding amino acid residue distance value storage means and / or the three-dimensional structure information of the known protein. Distance value reference affinity calculating means for calculating using
The vaccine candidate partial sequence prediction apparatus according to any one of claims 6 to 8, further comprising: The MHC binding partial sequence predicting means comprises:
A major histocompatibility determining means for determining the type of said particular major histocompatibility antigen;
MHC three-dimensional structure acquisition means for acquiring MHC three-dimensional structure information which is the three-dimensional structure of the main histocompatibility antigen determined by the main histocompatibility antigen determination means;
Based on the MHC three-dimensional structure information acquired by the MHC three-dimensional structure acquisition means and the partial sequence of the target sequence acquired by the target sequence acquisition means, a complex of the major histocompatibility antigen and the partial sequence A composite 3D structure creating means for creating 3D structure information;
In the complex three-dimensional structure information created by the complex three-dimensional structure creating means, a structure that is information about an index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information using a quantum chemical calculation method A structure evaluation index calculating means for calculating evaluation index value information;
A structure evaluation index reference MHC binding partial sequence prediction means for predicting the MHC binding partial sequence from the partial sequences based on the structure evaluation index value information calculated by the structure evaluation index calculation means;
The vaccine candidate partial sequence prediction apparatus according to any one of claims 1 to 3, further comprising: The non-self-recognizing partial sequence predicting means includes:
Specific biological species sequence storage means for storing specific biological species sequence information that is information relating to the specific biological species amino acid sequence that is the amino acid sequence of the specific biological species;
By performing a search of the partial sequence of the target sequence acquired by the target sequence acquisition unit with respect to the specific species sequence information stored by the specific species sequence storage unit, a score at the time of search is obtained. A non-self-recognition partial sequence search means for obtaining a certain non-self-recognition search score information;
Based on the non-self-recognition search score information acquired by the non-self-recognition partial sequence search unit, a search reference non-self-recognition partial sequence prediction unit that predicts the non-self-recognition partial sequence from the partial sequence;
The vaccine candidate partial sequence prediction apparatus according to any one of claims 1 to 10, further comprising: A target sequence acquisition step of acquiring target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide;
From the target sequence information acquired in the target sequence acquisition step, the amino acid sequence that is not cleaved by a proteolytic enzyme or proteosome present in the lysosome and predicts a non-cleavable partial sequence that is a partial sequence of the target sequence An uncut subsequence prediction step;
Based on the target sequence information acquired in the target sequence acquisition step, the amino acid sequence capable of binding to a specific major histocompatibility antigen, and an MHC binding partial sequence that is a partial sequence of the target sequence is predicted An MHC binding subsequence prediction step;
A non-self-recognizing partial sequence prediction step for predicting a non-self-recognizing partial sequence that is the amino acid sequence that is not recognized as self from the target sequence information acquired by the target sequence acquisition step and that is a partial sequence of the target sequence; ,
A non-mutated partial sequence prediction step for predicting a non-mutated partial sequence that is a partial sequence of the target sequence, which is the amino acid sequence that is difficult to be mutated, from the target sequence information acquired by the target sequence acquisition step When,
The non-cut partial sequence predicted by the non-cut partial sequence prediction step, the MHC binding partial sequence predicted by the MHC binding partial sequence prediction step, and the non-self recognition predicted by the non-self recognition partial sequence prediction step. Vaccine candidate partial sequence prediction for predicting a vaccine candidate partial sequence that is the amino acid sequence effective as a vaccine based on the partial sequence and / or the non-mutated partial sequence predicted by the non-mutated partial sequence prediction step Steps,
A method for predicting a partial sequence of a vaccine candidate. The non-cut partial sequence prediction step includes:
A cleavage site-containing sequence storage step for storing cleavage site-containing sequence information, which is information relating to the cleavage site-containing sequence, which is the amino acid sequence including several residues before and after the enzyme cleavage site, which is a site cleaved by the proteolytic enzyme;
A cleavage site-containing sequence that calculates cleavage site-containing sequence amino acid appearance frequency information that is information on the appearance frequency of amino acids at positions corresponding to each amino acid residue in the cleavage site-containing sequence stored in the cleavage site-containing sequence storage step An amino acid appearance frequency calculating step;
Based on the cleavage site-containing sequence amino acid appearance frequency information calculated in the cleavage site-containing sequence amino acid appearance frequency calculation step, a cleavage site-containing sequence score calculation step for calculating cleavage site-containing sequence score information;
Each partial sequence obtained by dividing the target sequence obtained by the target sequence acquisition step into the length of the cleavage site-containing sequence based on the cleavage site-containing sequence score information calculated by the cleavage site-containing sequence score calculation step A cleavage site-containing sequence length partial sequence score calculation step for calculating a cleavage site-containing sequence length partial sequence score information corresponding to:
Determine the enzyme cleavage site based on the cleavage site-containing sequence length partial sequence score information calculated in the cleavage site-containing sequence length partial sequence score calculation step, and the partial sequence cleaved at the enzyme cleavage site is not cleaved. A score-based non-cutting partial sequence prediction step for predicting as a partial sequence;
The vaccine candidate partial sequence prediction method according to claim 12, further comprising: The non-cut partial sequence prediction step includes:
A cleavage site sequence storage step for storing cleavage site sequence information that is information relating to the cleavage site sequence that is the amino acid sequence of the enzyme cleavage site that is a site cleaved by the proteolytic enzyme;
A cutting site motif sequence extracting step for extracting a known cutting site motif sequence from the cutting site sequence information stored by the cutting site sequence storing step,
The enzyme cleavage site in the target sequence by performing a motif search on the target sequence obtained in the target sequence acquisition step using the cleavage site motif sequence extracted in the cleavage site motif sequence extraction step Cutting site motif search step for acquiring cutting site search score information that is a score at the time of searching,
The enzyme cleavage site of the target sequence is determined based on the cleavage site search score information acquired by the cleavage site motif search step, and a partial sequence cleaved at the enzyme cleavage site is predicted as the non-cleavable partial sequence Motif search criterion non-cutting partial sequence prediction step;
The vaccine candidate partial sequence prediction method according to claim 12, further comprising: The MHC binding partial sequence prediction step includes:
A major histocompatibility antigen determining step to determine the type of the particular major histocompatibility antigen;
MHC binding which is information on the MHC binding site-containing sequence which is the amino acid sequence including several residues before and after the MHC binding site which is the site binding to the major histocompatibility antigen determined by the major histocompatibility antigen determination step An MHC binding site-containing sequence storage step for storing site-containing sequence information;
MHC for calculating MHC binding site-containing sequence amino acid appearance frequency information, which is information on the appearance frequency of amino acids at positions corresponding to each amino acid residue in the MHC binding site-containing sequence stored in the MHC binding site-containing sequence storage step A binding site-containing sequence amino acid appearance frequency calculating step;
An MHC binding site-containing sequence score calculation step for calculating MHC binding site-containing sequence score information based on the MHC binding site-containing sequence amino acid appearance frequency information calculated in the MHC binding site-containing sequence amino acid appearance frequency calculation step;
Based on the MHC binding site-containing sequence score information calculated in the MHC binding site-containing sequence score calculation step, the target sequence acquired in the target sequence acquisition step is divided into lengths of the MHC binding site-containing sequence. MHC binding site-containing sequence length partial sequence score calculating step for calculating MHC binding site-containing sequence length partial sequence score information corresponding to each partial sequence;
The MHC binding site-containing sequence length partial sequence score calculation step determines the MHC binding site based on the MHC binding site-containing sequence length partial sequence score information, and the partial sequence including the MHC binding site is determined as the MHC binding site. A score-based MHC binding subsequence prediction step for predicting as a binding subsequence;
The vaccine candidate partial sequence prediction method according to any one of claims 12 to 14, further comprising: The MHC binding partial sequence prediction step includes:
A major histocompatibility antigen determining step to determine the type of the particular major histocompatibility antigen;
An MHC that stores MHC binding site sequence information that is information about the MHC binding site sequence that is the amino acid sequence of the MHC binding site that is the site that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determination step A binding site sequence storing step;
An MHC binding site motif sequence extraction step for extracting a known MHC binding site motif sequence from the MHC binding site sequence information stored by the MHC binding site sequence storage step;
Using the MHC binding site motif sequence extracted in the MHC binding site motif sequence extraction step, performing a motif search on the target sequence acquired in the target sequence acquisition step, the MHC in the target sequence An MHC binding site motif search step of searching for a binding site and obtaining MHC binding site search score information that is a score at the time of search;
Motif search criteria for determining the MHC binding site based on the MHC binding site search score information acquired by the MHC binding site motif search step and predicting the partial sequence including the MHC binding site as the MHC binding partial sequence An MHC binding subsequence prediction step;
The vaccine candidate partial sequence prediction method according to any one of claims 12 to 14, further comprising: The MHC binding partial sequence prediction step includes:
A major histocompatibility antigen determining step to determine the type of the particular major histocompatibility antigen;
An MHC sequence acquisition step of acquiring main histocompatibility antigen sequence information, which is information on the main histocompatibility antigen sequence that is the amino acid sequence of the main histocompatibility antigen determined by the main histocompatibility antigen determination step;
Dividing the target sequence acquired in the target sequence acquisition step into lengths corresponding to the types of the main histocompatibility antigen determined in the main histocompatibility antigen determination step, and creating an MHC long partial sequence An MHC length partial sequence creation step;
Complex three-dimensional structure prediction for predicting complex three-dimensional structure information based on each MHC long partial sequence created by the MHC long partial sequence creating step and the major histocompatibility antigen sequence obtained by the MHC sequence obtaining step Steps,
Based on the complex three-dimensional structure information predicted by the complex three-dimensional structure prediction step, information on the set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence. An interacting amino acid determination step for determining certain interacting amino acid information;
Affinity information, which is information related to the affinity between the amino acid pairs included in the interacting amino acid information determined in the interacting amino acid determination step, is statistically calculated using the three-dimensional structure information of known proteins. An affinity calculation step;
An affinity sum total calculating step for calculating the sum of the affinity information among all the amino acid pairs calculated in the affinity calculating step;
Affinity for predicting the MHC binding partial sequence by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on the total of the affinity information calculated by the affinity total calculation step A reference MHC binding subsequence prediction step;
The vaccine candidate partial sequence prediction method according to any one of claims 12 to 14, further comprising: The MHC length partial sequence creation step includes:
The target sequence acquired in the target sequence acquisition step is divided into the length corresponding to the type of the major histocompatibility antigen while sliding the amino acid residues one by one from the beginning, and the MHC long partial sequence is Slide split step to create,
The vaccine candidate partial sequence prediction method according to claim 17, further comprising: The length corresponding to the type of major histocompatibility antigen is 8-18 residues,
The vaccine candidate partial sequence prediction method according to claim 17 or 18. The MHC binding partial sequence prediction step includes:
Information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determination step and each amino acid residue of the major histocompatibility antigen sequence A MHC-binding amino acid residue distance value storage step for storing MHC-binding amino acid residue distance value information,
Further including
The affinity calculation step includes
Statistical potential using the MHC binding amino acid residue distance value information stored in the MHC binding amino acid residue distance value storage step and / or the known three-dimensional structure information of the protein. A distance value reference affinity calculation step to calculate using
The vaccine candidate partial sequence prediction method according to any one of claims 17 to 19, further comprising: The MHC binding partial sequence prediction step includes:
A major histocompatibility antigen determining step to determine the type of the particular major histocompatibility antigen;
An MHC three-dimensional structure acquisition step of acquiring MHC three-dimensional structure information that is a three-dimensional structure of the main histocompatibility antigen determined by the main histocompatibility antigen determination step;
Based on the MHC three-dimensional structure information acquired in the MHC three-dimensional structure acquisition step and the partial sequence of the target sequence acquired in the target sequence acquisition step, a complex of the major histocompatibility antigen and the partial sequence A composite 3D structure creation step for creating 3D structure information;
In the complex three-dimensional structure information created by the complex three-dimensional structure creation step, a structure that is information on an index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information using a quantum chemical calculation method A structure evaluation index calculation step for calculating evaluation index value information;
A structure evaluation index reference MHC binding partial sequence prediction step for predicting the MHC binding partial sequence from the partial sequences based on the structure evaluation index value information calculated by the structure evaluation index calculation step;
The vaccine candidate partial sequence prediction method according to any one of claims 12 to 14, further comprising: The non-self-recognizing partial sequence prediction step includes:
A specific species sequence storing step for storing specific species sequence information, which is information relating to a specific species amino acid sequence, which is the amino acid sequence of the specific species;
By performing a search of the partial sequence of the target sequence acquired by the target sequence acquisition step with respect to the specific biological sequence information stored by the specific species sequence storage step, the score at the time of search is obtained. A non-self-recognition subsequence search step for obtaining certain non-self-recognition search score information;
Based on the non-self-recognition search score information acquired by the non-self-recognition partial sequence search step, a search reference non-self-recognition partial sequence prediction step for predicting the non-self-recognition partial sequence from the partial sequences;
The vaccine candidate partial sequence prediction method according to any one of claims 12 to 21, further comprising: A target sequence acquisition step of acquiring target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide;
From the target sequence information acquired in the target sequence acquisition step, the amino acid sequence that is not cleaved by a proteolytic enzyme or proteosome present in the lysosome and predicts a non-cleavable partial sequence that is a partial sequence of the target sequence An uncut subsequence prediction step;
Based on the target sequence information acquired in the target sequence acquisition step, the amino acid sequence capable of binding to a specific major histocompatibility antigen, and an MHC binding partial sequence that is a partial sequence of the target sequence is predicted An MHC binding subsequence prediction step;
A non-self-recognizing partial sequence prediction step for predicting a non-self-recognizing partial sequence that is the amino acid sequence that is not recognized as self from the target sequence information acquired by the target sequence acquisition step and that is a partial sequence of the target sequence; ,
A non-mutated partial sequence prediction step for predicting a non-mutated partial sequence that is a partial sequence of the target sequence, which is the amino acid sequence that is difficult to be mutated, from the target sequence information acquired by the target sequence acquisition step When,
The non-cut partial sequence predicted by the non-cut partial sequence prediction step, the MHC binding partial sequence predicted by the MHC binding partial sequence prediction step, and the non-self recognition predicted by the non-self recognition partial sequence prediction step. Vaccine candidate partial sequence prediction for predicting a vaccine candidate partial sequence that is the amino acid sequence effective as a vaccine based on the partial sequence and / or the non-mutated partial sequence predicted by the non-mutated partial sequence prediction step Steps,
A program for causing a computer to execute a vaccine candidate partial sequence prediction method including: The non-cut partial sequence prediction step includes:
A cleavage site-containing sequence storage step for storing cleavage site-containing sequence information, which is information relating to the cleavage site-containing sequence, which is the amino acid sequence including several residues before and after the enzyme cleavage site, which is a site cleaved by the proteolytic enzyme;
A cleavage site-containing sequence that calculates cleavage site-containing sequence amino acid appearance frequency information that is information on the appearance frequency of amino acids at positions corresponding to each amino acid residue in the cleavage site-containing sequence stored in the cleavage site-containing sequence storage step An amino acid appearance frequency calculating step;
Based on the cleavage site-containing sequence amino acid appearance frequency information calculated in the cleavage site-containing sequence amino acid appearance frequency calculation step, a cleavage site-containing sequence score calculation step for calculating cleavage site-containing sequence score information;
Each partial sequence obtained by dividing the target sequence obtained by the target sequence acquisition step into the length of the cleavage site-containing sequence based on the cleavage site-containing sequence score information calculated by the cleavage site-containing sequence score calculation step A cleavage site-containing sequence length partial sequence score calculation step for calculating a cleavage site-containing sequence length partial sequence score information corresponding to:
Determine the enzyme cleavage site based on the cleavage site-containing sequence length partial sequence score information calculated in the cleavage site-containing sequence length partial sequence score calculation step, and the partial sequence cleaved at the enzyme cleavage site is not cleaved. A score-based non-cutting partial sequence prediction step for predicting as a partial sequence;
The program according to claim 23, further comprising: The non-cut partial sequence prediction step includes:
A cleavage site sequence storage step for storing cleavage site sequence information that is information relating to the cleavage site sequence that is the amino acid sequence of the enzyme cleavage site that is a site cleaved by the proteolytic enzyme;
A cutting site motif sequence extracting step for extracting a known cutting site motif sequence from the cutting site sequence information stored by the cutting site sequence storing step,
The enzyme cleavage site in the target sequence by performing a motif search on the target sequence obtained in the target sequence acquisition step using the cleavage site motif sequence extracted in the cleavage site motif sequence extraction step Cutting site motif search step for acquiring cutting site search score information that is a score at the time of searching,
The enzyme cleavage site of the target sequence is determined based on the cleavage site search score information acquired by the cleavage site motif search step, and a partial sequence cleaved at the enzyme cleavage site is predicted as the non-cleavable partial sequence Motif search criterion non-cutting partial sequence prediction step;
The program according to claim 23, further comprising: The MHC binding partial sequence prediction step includes:
A major histocompatibility antigen determining step to determine the type of the particular major histocompatibility antigen;
MHC binding which is information on the MHC binding site-containing sequence which is the amino acid sequence including several residues before and after the MHC binding site which is the site binding to the major histocompatibility antigen determined by the major histocompatibility antigen determination step An MHC binding site-containing sequence storage step for storing site-containing sequence information;
MHC for calculating MHC binding site-containing sequence amino acid appearance frequency information, which is information on the appearance frequency of amino acids at positions corresponding to each amino acid residue in the MHC binding site-containing sequence stored in the MHC binding site-containing sequence storage step A binding site-containing sequence amino acid appearance frequency calculating step;
An MHC binding site-containing sequence score calculation step for calculating MHC binding site-containing sequence score information based on the MHC binding site-containing sequence amino acid appearance frequency information calculated in the MHC binding site-containing sequence amino acid appearance frequency calculation step;
Based on the MHC binding site-containing sequence score information calculated in the MHC binding site-containing sequence score calculation step, the target sequence acquired in the target sequence acquisition step is divided into lengths of the MHC binding site-containing sequence. MHC binding site-containing sequence length partial sequence score calculating step for calculating MHC binding site-containing sequence length partial sequence score information corresponding to each partial sequence;
The MHC binding site-containing sequence length partial sequence score calculation step determines the MHC binding site based on the MHC binding site-containing sequence length partial sequence score information, and the partial sequence including the MHC binding site is determined as the MHC binding site. A score-based MHC binding subsequence prediction step for predicting as a binding subsequence;
The program according to any one of claims 23 to 25, further comprising: The MHC binding partial sequence prediction step includes:
A major histocompatibility antigen determining step to determine the type of the particular major histocompatibility antigen;
An MHC that stores MHC binding site sequence information that is information about the MHC binding site sequence that is the amino acid sequence of the MHC binding site that is the site that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determination step A binding site sequence storing step;
An MHC binding site motif sequence extraction step for extracting a known MHC binding site motif sequence from the MHC binding site sequence information stored by the MHC binding site sequence storage step;
Using the MHC binding site motif sequence extracted in the MHC binding site motif sequence extraction step, performing a motif search on the target sequence acquired in the target sequence acquisition step, the MHC in the target sequence An MHC binding site motif search step of searching for a binding site and obtaining MHC binding site search score information that is a score at the time of search;
Motif search criteria for determining the MHC binding site based on the MHC binding site search score information acquired by the MHC binding site motif search step and predicting the partial sequence including the MHC binding site as the MHC binding partial sequence An MHC binding subsequence prediction step;
The program according to any one of claims 23 to 25, further comprising: The MHC binding partial sequence prediction step includes:
A major histocompatibility antigen determining step to determine the type of the particular major histocompatibility antigen;
An MHC sequence obtaining step for obtaining major histocompatibility antigen sequence information, which is information relating to the major histocompatibility antigen sequence that is the amino acid sequence of the major histocompatibility antigen determined by the major histocompatibility antigen determination step;
Dividing the target sequence acquired in the target sequence acquisition step into lengths corresponding to the types of the main histocompatibility antigen determined in the main histocompatibility antigen determination step, and creating an MHC long partial sequence An MHC length partial sequence creation step;
Complex three-dimensional structure prediction for predicting complex three-dimensional structure information based on each MHC long partial sequence created by the MHC long partial sequence creating step and the major histocompatibility antigen sequence obtained by the MHC sequence obtaining step Steps,
Based on the complex three-dimensional structure information predicted by the complex three-dimensional structure prediction step, information on the set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence. An interacting amino acid determination step for determining certain interacting amino acid information;
Affinity information, which is information related to the affinity between the amino acid pairs included in the interacting amino acid information determined in the interacting amino acid determination step, is statistically calculated using the three-dimensional structure information of known proteins. An affinity calculation step;
An affinity sum total calculating step for calculating the sum of the affinity information among all the amino acid pairs calculated in the affinity calculating step;
Affinity for predicting the MHC binding partial sequence by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on the total of the affinity information calculated by the affinity total calculation step A reference MHC binding subsequence prediction step;
The program according to any one of claims 23 to 25, further comprising: The MHC length partial sequence creation step includes:
The target sequence acquired in the target sequence acquisition step is divided into the length corresponding to the type of the major histocompatibility antigen while sliding the amino acid residues one by one from the beginning, and the MHC long partial sequence is Slide split step to create,
The program according to claim 28, further comprising: The length corresponding to the type of major histocompatibility antigen is 8-18 residues,
30. The program according to claim 28 or 29. The MHC binding partial sequence prediction step includes:
Information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determination step and each amino acid residue of the major histocompatibility antigen sequence A MHC-binding amino acid residue distance value storage step for storing MHC-binding amino acid residue distance value information,
Further including
The affinity calculation step includes
Statistical potential using the MHC binding amino acid residue distance value information stored in the MHC binding amino acid residue distance value storage step and / or the known three-dimensional structure information of the protein. A distance value reference affinity calculation step to calculate using
The program according to claim 28, further comprising: The MHC binding partial sequence prediction step includes:
A major histocompatibility antigen determining step to determine the type of the particular major histocompatibility antigen;
An MHC three-dimensional structure acquisition step of acquiring MHC three-dimensional structure information that is a three-dimensional structure of the main histocompatibility antigen determined by the main histocompatibility antigen determination step;
Based on the MHC three-dimensional structure information acquired in the MHC three-dimensional structure acquisition step and the partial sequence of the target sequence acquired in the target sequence acquisition step, a complex of the major histocompatibility antigen and the partial sequence A composite 3D structure creation step for creating 3D structure information;
In the complex three-dimensional structure information created by the complex three-dimensional structure creation step, a structure that is information on an index value for evaluating the three-dimensional structure corresponding to the complex three-dimensional structure information using a quantum chemical calculation method A structure evaluation index calculation step for calculating evaluation index value information;
A structure evaluation index reference MHC binding partial sequence prediction step for predicting the MHC binding partial sequence from the partial sequences based on the structure evaluation index value information calculated by the structure evaluation index calculation step;
The program according to any one of claims 23 to 25, further comprising: The non-self-recognizing partial sequence prediction step includes:
A specific species sequence storing step for storing specific species sequence information, which is information relating to a specific species amino acid sequence, which is the amino acid sequence of the specific species;
By performing a search of the partial sequence of the target sequence acquired by the target sequence acquisition step with respect to the specific biological sequence information stored by the specific species sequence storage step, the score at the time of search is obtained. A non-self-recognition subsequence search step for obtaining certain non-self-recognition search score information;
Based on the non-self-recognition search score information acquired by the non-self-recognition partial sequence search step, a search reference non-self-recognition partial sequence prediction step for predicting the non-self-recognition partial sequence from the partial sequences;
The program according to any one of claims 23 to 32, further comprising:   34. A computer-readable recording medium on which the program according to any one of claims 23 to 33 is recorded. A target sequence acquisition means for acquiring target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide;
A major histocompatibility determining means for determining the type of a particular major histocompatibility antigen;
MHC sequence acquisition means for acquiring main histocompatibility antigen sequence information, which is information on the main histocompatibility antigen sequence that is the amino acid sequence of the main histocompatibility antigen determined by the main histocompatibility antigen determination means;
Dividing the target sequence obtained by the target sequence obtaining means into lengths corresponding to the types of the major histocompatibility antigens determined by the major histocompatibility antigen determining means, and creating an MHC long partial sequence MHC length partial sequence creating means
Complex three-dimensional structure prediction for predicting complex three-dimensional structure information based on each MHC long partial sequence created by the MHC long partial sequence creating means and the major histocompatibility antigen sequence obtained by the MHC sequence obtaining means Means,
Based on the complex three-dimensional structure information predicted by the complex three-dimensional structure prediction means, information on the set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence. An interacting amino acid determining means for determining certain interacting amino acid information;
Affinity information, which is information related to the affinity between the amino acid pairs included in the interacting amino acid information determined by the interacting amino acid determining means, is statistically calculated using the three-dimensional structure information of a known protein. An affinity calculation means;
An affinity sum calculation means for calculating the sum of the affinity information among all the amino acid pairs calculated by the affinity calculation means;
The specific major histocompatibility antigen is evaluated by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on the sum of the affinity information calculated by the affinity summation calculation means. An affinity reference MHC binding partial sequence predicting means for predicting an MHC binding partial sequence which is the amino acid sequence capable of binding to
An MHC binding partial sequence prediction apparatus comprising: The MHC long partial sequence creating means includes:
The target sequence acquired by the target sequence acquisition means is divided into the length corresponding to the type of the major histocompatibility antigen while sliding by one amino acid residue from the beginning, and the MHC long partial sequence is Slide dividing means to create,
36. The MHC binding partial sequence prediction apparatus according to claim 35, further comprising: The length corresponding to the type of major histocompatibility antigen is 8-18 residues,
37. The MHC binding subsequence prediction apparatus according to claim 35 or 36. Information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determining means and each amino acid residue of the major histocompatibility antigen sequence MHC binding amino acid residue distance value storage means for storing MHC binding amino acid residue distance value information,
Further comprising
The affinity calculation means is:
Statistical potential using the MHC binding amino acid residue distance value information stored in the MHC binding amino acid residue distance value storage means and / or the three-dimensional structure information of the known protein. Distance value reference affinity calculating means for calculating using
The MHC binding subsequence prediction apparatus according to any one of claims 35 to 37, further comprising: A target sequence acquisition step of acquiring target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide;
A major histocompatibility antigen determining step to determine a particular major histocompatibility antigen type;
An MHC sequence obtaining step for obtaining major histocompatibility antigen sequence information, which is information relating to the major histocompatibility antigen sequence that is the amino acid sequence of the major histocompatibility antigen determined by the major histocompatibility antigen determination step;
Dividing the target sequence acquired in the target sequence acquisition step into lengths corresponding to the types of the main histocompatibility antigen determined in the main histocompatibility antigen determination step, and creating an MHC long partial sequence An MHC length partial sequence creation step;
Complex three-dimensional structure prediction for predicting complex three-dimensional structure information based on each MHC long partial sequence created by the MHC long partial sequence creating step and the major histocompatibility antigen sequence obtained by the MHC sequence obtaining step Steps,
Based on the complex three-dimensional structure information predicted by the complex three-dimensional structure prediction step, information on the set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence. An interacting amino acid determination step for determining certain interacting amino acid information;
Affinity information, which is information related to the affinity between the amino acid pairs included in the interacting amino acid information determined in the interacting amino acid determination step, is statistically calculated using the three-dimensional structure information of known proteins. An affinity calculation step;
An affinity sum total calculating step for calculating the sum of the affinity information among all the amino acid pairs calculated in the affinity calculating step;
The specific major histocompatibility antigen is evaluated by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on the sum of the affinity information calculated by the affinity summation calculation step. An affinity reference MHC binding partial sequence prediction step for predicting an MHC binding partial sequence that is the amino acid sequence capable of binding to
A method for predicting an MHC binding partial sequence, comprising: The MHC length partial sequence creation step includes:
The target sequence acquired in the target sequence acquisition step is divided into the length corresponding to the type of the major histocompatibility antigen while sliding the amino acid residues one by one from the beginning, and the MHC long partial sequence is Slide split step to create,
40. The method for predicting an MHC binding partial sequence according to claim 39, further comprising: The length corresponding to the type of major histocompatibility antigen is 8-18 residues,
41. The method for predicting an MHC binding partial sequence according to claim 39 or 40, wherein: Information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determination step and each amino acid residue of the major histocompatibility antigen sequence A MHC-binding amino acid residue distance value storage step for storing MHC-binding amino acid residue distance value information,
Further including
The affinity calculation step includes
Statistical potential using the MHC binding amino acid residue distance value information stored in the MHC binding amino acid residue distance value storage step and / or the known three-dimensional structure information of the protein. A distance value reference affinity calculation step to calculate using
The MHC binding partial sequence prediction method according to any one of claims 39 to 41, further comprising: A target sequence acquisition step of acquiring target sequence information, which is information on a target sequence that is an amino acid sequence of a target protein or physiologically active polypeptide;
A major histocompatibility antigen determining step to determine a particular major histocompatibility antigen type;
An MHC sequence obtaining step for obtaining major histocompatibility antigen sequence information, which is information relating to the major histocompatibility antigen sequence that is the amino acid sequence of the major histocompatibility antigen determined by the major histocompatibility antigen determination step;
Dividing the target sequence acquired in the target sequence acquisition step into lengths corresponding to the types of the main histocompatibility antigen determined in the main histocompatibility antigen determination step, and creating an MHC long partial sequence An MHC length partial sequence creation step;
Complex three-dimensional structure prediction for predicting complex three-dimensional structure information based on each MHC long partial sequence created by the MHC long partial sequence creating step and the major histocompatibility antigen sequence obtained by the MHC sequence obtaining step Steps,
Based on the complex three-dimensional structure information predicted by the complex three-dimensional structure prediction step, information on the set of amino acids interacting between the MHC long partial sequence and the major histocompatibility antigen sequence. An interacting amino acid determination step for determining certain interacting amino acid information;
Affinity information, which is information related to the affinity between the amino acid pairs included in the interacting amino acid information determined in the interacting amino acid determination step, is statistically calculated using the three-dimensional structure information of known proteins. An affinity calculation step;
An affinity sum total calculating step for calculating the sum of the affinity information among all the amino acid pairs calculated in the affinity calculating step;
The specific major histocompatibility antigen is evaluated by evaluating the affinity between the MHC long partial sequence and the major histocompatibility antigen based on the sum of the affinity information calculated by the affinity summation calculation step. An affinity reference MHC binding partial sequence prediction step for predicting an MHC binding partial sequence that is the amino acid sequence capable of binding to
A program for causing a computer to execute an MHC binding partial sequence prediction method including The MHC length partial sequence creation step includes:
The target sequence acquired in the target sequence acquisition step is divided into the length corresponding to the type of the major histocompatibility antigen while sliding the amino acid residues one by one from the beginning, and the MHC long partial sequence is Slide split step to create,
44. The program according to claim 43, further comprising: The length corresponding to the type of major histocompatibility antigen is 8-18 residues,
45. The program according to claim 43 or 44, wherein: Information on the distance value between each amino acid residue of the amino acid sequence that binds to the major histocompatibility antigen determined by the major histocompatibility antigen determination step and each amino acid residue of the major histocompatibility antigen sequence A MHC-binding amino acid residue distance value storage step for storing MHC-binding amino acid residue distance value information,
Further including
The affinity calculation step includes
Statistical potential using the MHC binding amino acid residue distance value information stored in the MHC binding amino acid residue distance value storage step and / or the known three-dimensional structure information of the protein. A distance value reference affinity calculation step to calculate using
The program according to claim 43, further comprising:   47. A computer-readable recording medium on which the program according to any one of claims 43 to 46 is recorded.

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