WO2002054063A1 - Systeme de base de donnees et methode utiles pour predire l'effet de substitutions d'un acide amine sur la structure et la stabilite de proteines - Google Patents

Systeme de base de donnees et methode utiles pour predire l'effet de substitutions d'un acide amine sur la structure et la stabilite de proteines Download PDF

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WO2002054063A1
WO2002054063A1 PCT/IL2001/001193 IL0101193W WO02054063A1 WO 2002054063 A1 WO2002054063 A1 WO 2002054063A1 IL 0101193 W IL0101193 W IL 0101193W WO 02054063 A1 WO02054063 A1 WO 02054063A1
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proteins
portions
amino acid
acid substitution
structurally characterized
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PCT/IL2001/001193
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English (en)
Inventor
Marvin Edelman
Eran Eyal
Rafael Najmanovich
Vladimir Sobolev
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Yeda Research And Development Co. Ltd.
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Publication of WO2002054063A1 publication Critical patent/WO2002054063A1/fr

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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment

Definitions

  • the present invention relates to a database system and method useful for predicting the effect of amino acid substitutions on a structure and a stability of a protein of interest.
  • Proteins are gene products which form an essential part of living organisms by contributing to cellular and tissue structure and participating in various cellular processes.
  • a critical feature of a protein is it's ability to fold into a three dimensional conformation which, in most cases, dictates and is essential for the function of the protein.
  • biologists utilize various mutational approaches to study the function of proteins of interest.
  • the effect of a particular mutation on the conformation of a protein can also be obtained and correlated to the effect of the mutation on protein function.
  • Such cases include proteins for which structural information has been obtained via, for example, X-ray crystallography or NMR spectra.
  • structural information is oftentimes difficult to obtain, the effect of an amino acid substitution on protein conformation cannot be readily obtained.
  • a method of predicting an effect of a specific amino acid substitution on a structure of a protein of interest the method is executed, at least in part, by a computer and comprising the steps of: (a) selecting at least one pair of structurally characterized proteins or portions of proteins, members of the at least one pair differing in at least the specific amino acid substitution; and (b) extracting data from the members, the data being useful in predicting the effect of the specific amino acid substitution on at least one structural parameter of at least a portion of the protein of interest.
  • the at least one pair of structurally characterized proteins or portions of proteins is selected from a database including a plurality of unique pairs of structurally characterized proteins or portions of proteins.
  • each of the plurality of unique pairs of the database is paired according to at least a specific amino acid substitution between members of the pair.
  • the step of selecting is effected according to the specific amino acid substitution or the identity of at least of the members of the at least one pair.
  • the step of selecting the at least one pair of structurally characterized proteins or portions of proteins is effected according to at least one criteria selected from the group consisting of a position of the amino acid substitution, an amino acid sequence flanking the amino acid substitution, a type of domain including the amino acid substitution, a function of the structurally characterized proteins or portions of proteins, a size of the structurally characterized proteins or portions of proteins, a ligand or ligands capable of binding the structurally characterized proteins or portions of proteins, identity between the structurally characterized proteins or portions of proteins and a file reference of the structurally characterized proteins or portions of proteins.
  • the data includes a change in atomic contacts as a result of the specific amino acid substitution.
  • the data includes a change in solvent accessibility as a result of the specific amino acid substitution.
  • the at least one structural parameter is selected from the group consisting of backbone flexibility, side chain flexibility, structural stability, and charge conductivity.
  • each of the plurality of unique pairs of the database is also paired according to at least one additional criteria selected from the group consisting of the position of the amino acid substitution, the identity of the proteins or portions of proteins, the size of the proteins or portions of protein, the structure of the proteins or portions of proteins and the function of the proteins or portions of proteins.
  • a data storage media comprising, as retrievable records, pairs of structurally characterized proteins or portions of proteins, each pair being paired according to at least a specific amino acid substitution between members thereof.
  • the data storage media further comprise as retrievable records, structural data of at least one of the structurally characterized proteins or portions of proteins.
  • the media is selected from the group consisting of a magnetic media, an optical media and an optical-magnetic media.
  • the optical media is a computer disk (CD) or a digital video disk (DVD).
  • each pair is also paired according to at least one additional criteria selected from the group consisting of the position of the amino acid substitution, the identity of the proteins or portions of proteins, the size of the proteins or portions of protein, the structure of the proteins or portions of proteins and the function of the proteins or portions of proteins.
  • a system useful for predicting an effect of a specific amino acid substitution on a structure or stability of a protein of interest comprising a computing platform including: (a) data storage media storing, as retrievable records, pairs of structurally characterized proteins or portions of proteins each pair being paired according to at least an amino acid substitution between members thereof; and (b) a data processor for executing a software application being for providing access to specific pairs of the pairs of structurally characterized proteins or portions of proteins, the specific pairs being paired according to at least the specific amino acid substitution between members thereof.
  • the software application is capable of generating a matrix including paired proteins or portions of proteins.
  • the software application is a search engine.
  • system further comprising a server communicating with or forming a part of, the computing platform, the server being capable of communicating with a user client being operated by a user for providing the user access to the retrievable records.
  • the server forms a part of a communication network.
  • the communication network is the World Wide Web.
  • the user client is a computer operating a Web browser application.
  • a method of generating a database useful for predicting an effect of a specific amino acid substitution on a structure or stability of a protein of interest the method being executed by a computer and comprising the steps of: (a) obtaining records including at least amino acid sequences of a plurality of structurally characterized proteins or portions of proteins; and (b) pairing structurally characterized proteins or portions of proteins according to at least an amino acid substitution between members of a pair thereby generating the database useful for predicting an effect of a specific amino acid substitution on a structure or the stability of a protein of interest.
  • the step of pairing is effected according to at least one additional criteria selected from the group consisting of the position of the amino acid substitution, the identity of the proteins or portions of proteins, the size of the proteins or portions of protein, the structure of the proteins or portions of proteins and the function of the proteins or portions of proteins.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing a database system and method useful for predicting the effect of amino acid substitution(s) on a structure or the stability of a protein of interest.
  • Implementation of the method and system of the present invention involves performing or completing selected tasks or steps manually, automatically, or a combination thereof.
  • several selected steps could be implemented by hardware or by software on any operating system of any firmware or a combination thereof.
  • selected steps of the invention could be implemented as a chip or a circuit.
  • selected steps of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system.
  • selected steps of the method and system of the invention could be described as being performed by a data processor, such as a computing platform for executing a plurality of instructions.
  • FIG. 1 is a black box diagram of the system of the present invention.
  • FIG. 2 is a matrix of protein data bank (PDB) file pairs representing proteins which differ by a single amino acid substitution between pair members.
  • the number in each cell is the amount of unique file pairs available for a specific amino acid substitution. Selection of a single cell (marked with an arrow) results in the Table shown in Figure 3.
  • PDB protein data bank
  • FIG. 3 is a table in which every line represents a pair of files which differ in an Asp to Gly substitution.
  • the first line shows a single pair of files representing wild type and mutant thymidylate synthase (the file lnjd and it's
  • FIG. 4 is a table which lists all residues in contact with the 'mutated' amino acid (Asp/Gly 229), along with the specific type of contact (e.g., hydrogen bond, hydrophobic, aromatic, etc.).
  • the root mean square (RMS) and maximal differences between paired atoms are also provided.
  • FIG. 5 is a CHIME generated three dimensional representation of the mutated region superimposed on the respective wild type region of thymidylate synthase.
  • the present invention is of a database, system and method which can be utilized to predict the effects of amino acid substitutions on protein structure or stability. Specifically, the present invention can be used to determine the effect of an amino acid substitution on, for example, the three dimensional conformation, backbone or side chain flexibility, thermal stability, solubility, hydrophobicity and/or hydrophilicity, charge conductivity, antigenic index or surface probability of a protein or a portion of a protein of interest.
  • the principles and operation of the present invention may be better understood with reference to the drawings and accompanying descriptions.
  • the inventors While reducing the present invention to practice, the inventors have collected data from the protein data bank and generated a database of paired files exhibiting one or more amino acid substitutions. Direct comparison of structural information derived from these files has yielded comparative data which is useful in predicting the effect of one or more amino acid substitutions on protein structure or stability.
  • a method of predicting an effect of one or more specific amino acid substitution on a structure or the stability of a protein or a portion of a protein of interest As used herein, the phrase "portion of a protein" refers to any portion defined by one to several hundred amino acids.
  • the method of the present invention is executed, at least in part, by a computing platform and is effected by selecting at least one pair of structurally characterized proteins or portions of proteins, wherein members of each pair differ in at least one specific amino acid substitution, and extracting data, such as, a change in atomic contacts, and/or atom contact type, and/or a change in solvent accessibility resulting from the specific amino acid substitution(s) between members of each selected pair.
  • this data is useful in predicting the effect of one or more specific amino acid substitutions on at least one structural parameter of at least a portion of the protein of interest.
  • structural parameter refers to a parameter which is effected by the inter-atomic contacts of the protein, including, but not limited to, three dimensional conformation, backbone or side chain flexibility, solubility, hydrophobicity and/or hydrophilicity, charge conductivity, antigenic index, surface probability or stability.
  • the pairs of structurally characterized proteins or portions of proteins are selected from a database which includes a plurality of unique pairs of structurally characterized proteins or portions.
  • Such a database is generated by obtaining records including at least amino acid substitutions of a plurality of structurally characterized proteins or portions of proteins and pairing the structurally characterized proteins or portions of proteins at least according to an amino acid substitution criteria between members of a pair.
  • Such pairing can also be effected according to additional criteria such as, but not limited to, the identity (e.g., PDB ID) of at least one member of the pair, the position of the amino acid substitution, the amino acid sequence flanking the amino acid substitution site, the type of domain including the amino acid substitution, the function of the protein, the size of the proteins or portion of the proteins, a ligand or ligands, or file reference.
  • identity e.g., PDB ID
  • the method of the present invention enables prediction of structural changes incurred by one or more amino acid substitutions.
  • Such predictions can be either restricted to a particular portion or subunit of the protein, including, for example: (i) a functional domain, such as a binding or a catalytic domain or a signal sequence; (ii) a structural domain, such as an o helix or a ⁇ sheet; or (iii) an antigenic domain, or it can be utilized to predict a structural change of the entire protein.
  • system 10 useful for predicting an effect of at least one specific amino acid substitution on a structure or the stability of a protein of interest, which system is referred to hereinunder as system 10.
  • System 10 includes a computing platform 12 which includes a data storage media 14 which can be, for example, a magnetic storage media, an optical storage media or a combination of both.
  • Data storage media 14 stores as retrievable records, pairs of structurally characterized proteins or portions of proteins, each paired as described above.
  • Data storage media 14 preferably further includes, as retrievable records, structural data of at least one, preferably all, of the structurally characterized proteins or portions of proteins.
  • structural data can include, data derived from X-ray crystallography, NMR spectra or theoretical models.
  • Computing platform 12 further includes a data processor which executes a software application which serves for providing access to specific pairs of the pairs of structurally characterized proteins or portions of proteins.
  • a software application can generate and provide a search interface such as, for example, a matrix of protein pairs (see, for example, Figure 2) or it can be a keyword, file name or author name search engine.
  • system 10 further includes a server 16 communicating with or forming a part of, computing platform 12.
  • Server 16 is capable of communicating with a user client 18 being operated by a user via a communication network 20.
  • communication network preferably refers to the Internet as manifested by the World Wide Web (WWW) of computers, although the system of the present invention can also be implemented within Intranets or Extranets or any other open or closed communication network.
  • WWW World Wide Web
  • the phrase "user client” generally refers to a computer and includes, but is not limited to, personal computers (PC) having an operating system such as DOS, Windows, OS/2 TI or Linux; Macintosh 1" ' computers; computers having JANA TI -OS as the operating system; and graphical workstations such as the computers of Sun Microsystems 71 and Silicon Graphics 1 ', and other computers having some version of the UNIX operating system such as AIX T ' or SOLARIS 1" ' of Sun Microsystems 1" '; or any other known and available operating system; personal digital assistants (PDA), cellular telephones having Internet capabilities (e.g., wireless application protocol, WAP) and Web TVs.
  • PC personal computers
  • PDA personal digital assistants
  • WAP wireless application protocol
  • server 16 provides a user of user client 18 with access to the retrievable records stored by data storage media 14. Preferably, such access is mediated by the software application described above.
  • the retrievable data stored by data storage media 14 is accessible via a Web site stored, maintained and operated by system 10.
  • a user preferably accesses the data via a Web browser application operating in user client 18.
  • Web browser or the term “browser” refers to any software application which can display text, graphics, or both (using built in features or dedicated plug-ins), from Web pages on World Wide Web sites. Examples of Web browsers include, Netscape navigator, Internet
  • Web site is used to refer to at least one Web page, and preferably a plurality of Web pages, virtually connected to form a coherent group of interlinked documents.
  • Web page refers to any document written in a mark-up language including, but not limited to, HTML (hypertext mark-up language) or VRML (virtual reality modeling language), dynamic HTML, XML (extended mark-up language) or related computer languages thereof, as well as to any collection of such documents reachable through one specific Internet address or at one specific World Wide Web site, or any document obtainable through a particular URL (Uniform Resource Locator).
  • HTML hypertext mark-up language
  • VRML virtual reality modeling language
  • XML extended mark-up language
  • URL Uniform Resource Locator
  • EXAMPLE 1 Database generation Data was collected from the PDB (Bernstein & Williams, 1977; Berman et ah, 2000) which relates to structural distinctions between proteins exhibiting a single amino acid difference.
  • a Web site has been created which permits rapid searching of this data with links to detailed structural analysis of the mutation site (http://bioinfo.weizmann.ac.il/MutaProt, the content of which is incorporated herein by references). This Web site has been created to facilitate accumulation of data and was kept confidential from the general public prior to filing of the instant application.
  • MutaProt 1 The database generated by the present invention, which is termed MutaProt 1"1 , includes pairs of PDB files that differ in one or more amino acids and which may or may not have identical ligands associated with the two proteins; crystallographic files of resolution 3.5 A or better were included. When initially created, MutaProt contained 9766 file pairs. The database is automatically updated on a weekly basis. Database search: MutaProt can be searched in two three separate ways: by selecting one or more pairs of amino acids representing a substitution, such as for example Asp and Gly from a matrix ( Figure 2), by entering keywords or by designating a particular PDB file ID.
  • Search results Using any of the search methods creates a table of entries matching the search parameters (Figure 3). A cell in the table will contain one or more pairs, depending on the number of PDB entries with the same sequence or the number of mutant files for the specific residue being queried. Accessing a specific file pair provides detailed structural information concerning the immediate environment of the mutation area. This includes the relative accessibility of the mutated residues, the displacement between equivalent atoms of the contacting residues, and a full list of contacts involving the mutated site and its surrounding residues ( Figure 4). A direct link to the relevant page of the CSU program (Sobolev et al., 1999) provides contact analysis down to the atom-atom level. Graphical presentation:
  • MutaProt employs CHIME (http://www.mdli.com) to visualize the superimposed mutated regions from both the wild type and mutated files. As shown in Figure 5, the presentation includes the amino acid pair undergoing change and their contacting residues. Superimposition is carried out by a software program of the present invention which utilizes minimization of root mean square differences using the flexible polyhedron search method (Himmelblau, 1972). The entire program was written in PERL using the CGI.pm module.
  • the present invention provides information relating to the influence of amino acid substitution on protein stability and backbone and side-chain flexibility. Such information is germane to planning site-directed-mutagenesis strategies and to the analysis of random mutations of proteins.
  • EXAMPLE 2 The effect of an Asp to Gly substitution
  • the present invention was utilized to analyze the structural changes effected as a result of an Aspartic acid to Glycine substitution using data acquired from PDB files of protein pairs exhibiting such substitution.
  • the database of the present invention provided, at the time accessed, 12 unique protein pairs for such a substitution. From these pairs (shown in Figure 3), data of the PDB files lnjd and ljmg of thymidylate synthase exhibiting Asp to Gly substitution at position 229 were selected for further analysis.
  • Figure 4 represents atomic contact data for the lnjd and ljmg PDB files, illustrating the changes in atomic contacts as a result of the amino acid substitution.
  • Figure 4 illustrates that potential hydrogen bonds which stabilize the interaction of Asp229 with its neighbors His 199, Gln217 and Ser232 are lost when Asp is substituted by Gly.
  • the CSU link supplied in Figure 4 was activated. Table 1 below, which is accessible via the CSU link describes the atomic contacts formed by Asp 229 in PDB entry lnjd.
  • the boxed data of Table 1 describes the potential hydrogen bond interaction of As ⁇ 229 with His 199, Gln217 and Ser 232.
  • An analysis of this data shows that strong hydrogen bond interaction occurs between the NE2 atom of His 199 and the ODl atom of Asp229 (distance, 2.7 A), and between the NE2 atom of Gln217 and the OD2 atom of Asp229 (distance, 3.1 A).
  • a distance of 5.3 A between the OG atom of Ser232 and the ODl atom of Asp229 would allow for a putative water-mediated hydrogen bond.
  • Substitution of Asp by Gly in thymidylate synthase leads to the loss of two actual hydrogen bonds and one putative hydrogen bond and an effect on protein stability.
  • Such bond substitution information providable by the present invention presents a valuable tool for predicting the effect of amino acid substitutions on protein structure and/or stability.
  • the present invention also provides graphical representation of the changes in protein structure, in the vicinity of the changed residue, as a result of the substitution ( Figure 5).
  • such graphical representation can provide visual information on changes in the torsion angles of the compared residues in the mutation site as well as the differences in the side-chain positions.
  • the contacts listed in Figure 4 can be visually identified.
  • contacting atoms The definition of non-covalent contacting atoms used by the present invention is based on Sobolev V. and Edelman M. (PROTEINS 21: 214-225, 1995).
  • Contact surface area between atoms A and B is defined as the area of a sphere whose center is the center of atom A and whose radius equals the sum of the Van der Waals radii of atom A and a solvent molecule. This area consists of points within which a solvent molecule would overlap with the Van der Waals sphere of atom B. If a solvent molecule cannot be placed at some particular point because it will penetrate several neighboring atoms, it is postulated that this point belongs to the contact area of atom A and the nearest of these neighboring atoms.
  • This definition implies that atoms, up to a distance RA +RB + 2RW (radius of atom A + radius of atom B + 2 x radius of solvent molecule) from a given atom may be in contact but the contact surface area will depend both on the distance between atoms and arrangement of nearest neighbors.
  • this definition of contacting atoms includes a parameter of 'legitimate' and 'illegitimate' contact types (based on Sobolev V., Wade R.C., Vriend G. and Edelman M. PROTEINS 25: 120-129, 1996).
  • CSU automated software
  • the present invention employs the CSU software to provide a list of residues in contact with a designated residue by analyzing contacts based on contacting atom types and contacting surface areas.
  • ProTherm defines non-covalent contacting atoms simply as atoms which fall within 0 to 8 A of each other.
  • the contact range prediction complexity of the present invention allows to define a more selective list of contacting atoms and a more accurate contact range (up to 6 A) and as such to substantially improve the predictability of the present invention.
  • Database architecture and orientation The present invention includes and employs a purely structural database of protein pairs, members of which are resolved and listed in the Protein DataBase (PDB), an international collection of resolved macromolecular structures. The two members of any protein pair are identical in sequence except for one, or more a few, amino acid differences. Consequently, the CSU structural analysis parameters employed by the present invention can be specifically related to these differences. (If a heterogroup [i.e., ligand] difference between pair members should also exist, a warning is provided).
  • PDB Protein DataBase
  • ProTherm collates thermodynamic data from the literature for pairs of proteins without consideration for the resolution of their structure. In fact, the great majority of ProTherm entries do not contain structural data.
  • one member of a ProTherm pair is always a 'wildtype' protein.
  • the visualization tool utilized by the MutaProt Web site embodiment of the present invention provides several additional advantages over the prior art as follows: (i) it provides results rapidly while being easy to use; (ii) it is specifically limited to the mutation area of the two pair members; and (iii) it provides an image of the mutated region superimposed upon the non-mutated region, such that structural differences between the pair members can be immediately detected and analyzed by the user.
  • ProTherm on the other hand, requires a user to download the files of interest to a local computer and to open each member of the pair separately before visualization can be achieved. Although an image of the entire protein can be obtained, ProTherm does not enable superimposition of the pair members or a portion thereof.
  • the present invention enables a user to obtain detailed analysis of atomic contact changes as a result of one or more amino acid substitutions while being able to view a superimposed 3D presentation of the regions being compared, thus greatly enhancing the ability of the user to predict the effect of an amino acid substitution on protein structure or stability.

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Abstract

La présente invention concerne une méthode de prédiction d'un effet d'une substitution d'un acide aminé spécifique, ou d'une mutation, sur une structure ou une stabilité de la protéine étudiée, ainsi que du matériel permettant de mettre en oeuvre ladite méthode. Cette méthode est mise en oeuvre, au moins en partie, à l'aide d'un ordinateur et consiste à (a) sélectionner au moins une paire de protéines ou de parties de protéines caractérisées structurellement, des éléments d'au moins une paire différente au moins au niveau de la substitution d'un acide aminé spécifique; et (b) à extraire des données des éléments, les données étant utiles pour prédire l'effet de la substitution d'un acide aminé spécifique sur au moins un paramètre structural d'au moins une partie de la protéine étudiée.
PCT/IL2001/001193 2001-01-04 2001-12-24 Systeme de base de donnees et methode utiles pour predire l'effet de substitutions d'un acide amine sur la structure et la stabilite de proteines WO2002054063A1 (fr)

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US20200411136A1 (en) * 2018-02-26 2020-12-31 Just Biotherapeutics, Inc. Determining impact on properties of proteins based on amino acid sequence modifications
CN117352043A (zh) * 2023-12-06 2024-01-05 江苏正大天创生物工程有限公司 基于神经网络的蛋白设计方法及系统

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US20200411136A1 (en) * 2018-02-26 2020-12-31 Just Biotherapeutics, Inc. Determining impact on properties of proteins based on amino acid sequence modifications
CN117352043A (zh) * 2023-12-06 2024-01-05 江苏正大天创生物工程有限公司 基于神经网络的蛋白设计方法及系统
CN117352043B (zh) * 2023-12-06 2024-03-05 江苏正大天创生物工程有限公司 基于神经网络的蛋白设计方法及系统

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