JP2007058273A - Aggregate model evaluation device for evaluating aggregate model among plurality of polypeptides, aggregate model evaluation method and aggregate model evaluation program - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a technology for accurately evaluating adaptability of a solid structural model of an aggregate of a plurality of polypeptides. <P>SOLUTION: This aggregate model evaluation device 100 is provided with an aggregate model acquisition part 102 which acquires the solid structural model of the aggregate generated based on each solid structural model of the plurality of polypeptides, a selection part 140 which selects the solid structural model of the aggregate with a ZDOCK evaluation component, an adaptability evaluation part 142 which evaluates the adaptability of the solid structural model of the aggregate with a Verify 3D program and a Prosa 2003 program, and an output part 134 which outputs a comprehensive adaptability index. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a conjugate model evaluation apparatus, a conjugate model evaluation method, and a conjugate model evaluation program for evaluating a conjugate model between a plurality of polypeptides.

  The three-dimensional structure of a protein is closely related to its function, and three-dimensional structure information is necessary for understanding the function at the molecular basis level. In addition, since most existing drugs interact with proteins, the three-dimensional structure of proteins can be used to investigate the binding mode of conjugates due to these interactions, or to know the chemical structure of small molecules that can become new drugs. Information is needed. As means for determining the three-dimensional structure of a protein, there are an experimental method such as X-ray analysis and a computer method such as molecular simulation.

  An example of a conventional binding site prediction apparatus relating to protein-protein binding prediction by such a computer technique is disclosed in Patent Document 1, for example. The binding site prediction apparatus described in the same document obtains spatial distance data between amino acid residues in the three-dimensional structure of the protein or bioactive polypeptide from the amino acid sequence data of the protein or bioactive polypeptide, and calculates the distance. Binding sites are predicted by identifying electrostatically unstable amino acid residues according to the data and the charge of each amino acid.

  Further, as a conventional function prediction support apparatus for predicting the binding of a protein-compound conjugate or a protein-polymer conjugate by a computer technique, for example, there is one described in Patent Document 2. The function prediction support apparatus described in the same document stores information (active site shape, electrostatic potential, hydrophobic region) and the like obtained from known documents and experimental results for individual proteins in a DB (database). Based on the information stored in the DB, the binding prediction of the protein-compound conjugate or the protein-polymer conjugate is performed.

  Moreover, as a conventional structure prediction apparatus regarding a three-dimensional structure prediction in consideration of the interaction between a protein and a ligand by a computer method, there is, for example, one described in Patent Document 3. The structure prediction apparatus described in this document treats a ligand as a rigid body that does not depend on the type of atoms in the process of creating a three-dimensional structure for simplification of a multi-chain protein including a single chain in a state in which the ligand is bound. By using parameters and functions that reflect the dynamic behavior of the protein, the three-dimensional structure prediction is performed in consideration of the calculation of the interaction between the protein and the ligand.

  Further, as a conventional binding prediction program related to protein binding prediction by a computer method, there is, for example, one described in Non-Patent Document 1. The binding prediction program described in this document is a protein-protein docking simulation software called ZDOCK developed by the Zhiping Weng group at Boston University. ZDOCK treats proteins as rigid bodies. Then, the binding site prediction is performed by controlling the rotation angle of each molecule as the Euler angle and performing FFT processing. In addition, bond structures are ranked based on electrostatic interaction energy and ACE desolvation energy.

JP 2004-109053 A JP 2004-152029 A JP 2004-258814 A Rong Chen and Zhiping Weng, “DockingUnbound Proteins Using Shape Complementarity, Desolvation, and Electrostatics”, PROTEINS: Structure, Function, and Genetics 47: 281−294 (2002)

However, the prior art described in the above literature has room for improvement in the following points.
First, the binding site prediction apparatus described in Patent Document 1 is based on the premise that an unstable portion in a protein is likely to be bound because it has the possibility of being stabilized by binding. Even if the protein is unstable, it is not always easy to bind to other proteins, so there is room for improvement in terms of prediction and evaluation accuracy. In addition, the binding site prediction apparatus described in Patent Document 1 only provides active site prediction (prediction information of a site corresponding to the so-called glue margin between proteins), and evaluates the validity of a protein conjugate model. It was difficult to do.

  Second, in the function prediction support apparatus described in Patent Document 2, information (active site shape, electrostatic potential, hydrophobic region) stored in a DB (database) is information about individual proteins. . For this reason, it is difficult to obtain accurate information about the state after docking of the protein-compound conjugate or protein-polymer conjugate based on this information, which improves the accuracy of prediction and evaluation. There was room for.

  Third, the structure prediction apparatus described in Patent Document 3 is a multi-chain protein including a single chain in a state in which a ligand is bound in a process for creating an entire three-dimensional structure for simplification, and the ligand is not dependent on the atomic type. Treat as a rigid body. In other words, since the atoms constituting the ligand molecule are treated as rigid bodies having an average atomic radius with no electrical polarity, the types of information used for protein-ligand bond prediction are limited, and the accuracy of prediction and evaluation is limited. There was room for improvement.

  Fourth, the binding prediction program described in Non-Patent Document 1 performs protein-protein docking simulation based on shape complementarity, electrostatic interaction energy, and ACE desolvation energy. There was still room for improvement in terms of evaluation accuracy.

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a technique for accurately evaluating the suitability of a three-dimensional structure model of a conjugate of a plurality of polypeptides.

  According to the present invention, there is provided a conjugate model evaluation apparatus for evaluating a conjugate model of a plurality of polypeptides, which is generated based on the three-dimensional structure model of each of the plurality of polypeptides. And the water solubility of the entire three-dimensional structure model of the conjugate based on the peripheral polarity for each amino acid residue and the degree of solvent exposure of the side chain for each amino acid residue in the three-dimensional structure model of the conjugate. The environmental conformity assessment unit that generates an environmental compatibility index for the sex and internal environment of the protein, and the distance-dependent potential energy for each amino acid residue pair in the conformational model of the conjugate, A distance-dependent potential energy evaluation unit that generates a distance-dependent potential energy index, and a ring of a three-dimensional structure model of a conjugate A comprehensive suitability evaluation unit that generates a comprehensive suitability index of the three-dimensional structure model of the conjugate based on the suitability index and the distance-dependent potential energy index; and an output unit that outputs the comprehensive suitability index. A combined model evaluation device is provided.

  According to this configuration, the environmental compatibility and distance-dependent potential energy normally used for evaluating the three-dimensional structure of a single polypeptide are evaluated for the entire three-dimensional structure model of the conjugate, and based on these, the three-dimensional structure of the conjugate is evaluated. Since the suitability of the model is evaluated, the suitability of the three-dimensional structure model of a conjugate of a plurality of polypeptides can be accurately evaluated.

  According to the present invention, there is provided a conjugate model evaluation apparatus for evaluating a conjugate model of a plurality of polypeptides, and a plurality of conjugate solids generated on the basis of the three-dimensional structure model of each of the plurality of polypeptides. A combination model acquisition unit for acquiring a structural model, a structural complementarity evaluation unit for generating a structural complementarity index of the conjugate based on the structural complementarity of each polypeptide in the three-dimensional structure model of the conjugate, and a plurality of A conjugate model selection unit for selecting a conjugate model having a structural complementarity index greater than or equal to a threshold value from the three-dimensional model of the conjugate of the conjugate, and a periphery for each amino acid residue in the stereostructure model of the selected conjugate Generates an environmental compatibility indicator for the water solubility of the entire conformational model of the conjugate and the internal environment of the protein based on the degree of polarity and solvent exposure of the side chain for each amino acid residue Environmental suitability evaluation unit, distance-dependent potential energy evaluation unit that generates a distance-dependent potential energy index for the entire three-dimensional model of the selected conjugate, and environmental suitability of the three-dimensional model of the selected conjugate A total suitability evaluation unit that generates a total suitability index of the three-dimensional structure model of the selected conjugate based on the index and the distance-dependent potential energy index; and an output unit that outputs the total suitability index A combined body model evaluation apparatus is provided.

  According to this configuration, based on the structural complementarity between the polypeptides, a three-dimensional structure model of a conjugate whose structural complementarity is equal to or higher than a predetermined level is selected, and the whole three-dimensional structure model of the selected conjugate is selected. In order to evaluate environmental compatibility and distance-dependent potential energy, and to evaluate the conformity of the three-dimensional structure model of the conjugate based on these, accurately evaluate the conformity of the three-dimensional structure model of the conjugate between multiple polypeptides. can do.

  Note that the above-described device is one embodiment of the present invention, and the device of the present invention may be any combination of the above components. Also, the conjugate model evaluation method, the conjugate model evaluation system, the conjugate model evaluation program, the recording medium, etc. of the present invention have the same configuration.

  In the present invention, a polypeptide is a substance containing a protein.

  According to the present invention, the environmental compatibility and the distance-dependent potential energy normally used for evaluating the three-dimensional structure of a single polypeptide are evaluated for the entire three-dimensional structure model of the conjugate, and based on this, the three-dimensional structure of the conjugate is evaluated. Since the suitability of the model is evaluated, the suitability of the three-dimensional structure model of a conjugate of a plurality of polypeptides can be accurately evaluated.

  In the present invention, the environmental compatibility evaluation unit further generates an environmental compatibility index for the water solubility of the entire three-dimensional structure model of the conjugate and the internal environment of the protein based on the secondary structure formed by the amino acid residue. Also good.

  According to this configuration, in addition to the peripheral polarity for each amino acid residue and the degree of solvent exposure of the side chain for each amino acid residue, environmental compatibility is evaluated based on the secondary structure formed by the amino acid residue. Therefore, the accuracy of evaluating the conformity of the three-dimensional structure model of a conjugate of a plurality of polypeptides is improved.

  In the present invention, the above-described conjugate model evaluation apparatus includes a structural complementarity evaluation unit that generates a structural complementarity index of a conjugate based on the structural complementarity between the polypeptides in the three-dimensional structure model of the conjugate. The comprehensive suitability evaluation unit described above may further generate a comprehensive suitability index based on the structural complementarity index.

  According to this configuration, in addition to environmental compatibility and distance-dependent potential energy, structural complementarity can be further evaluated. Therefore, the accuracy of evaluating the conformity of the three-dimensional model in a conjugate of a plurality of polypeptides can be improved. improves.

  Further, in the present invention, the structural complementarity evaluation unit described above includes the shape complementarity between the polypeptides, the desolvation between the polypeptides, and the electrostatic interaction between the polypeptides. Based on this, a structural complementarity index of the conjugate may be generated.

  According to this configuration, the above-described structural complementarity evaluation unit has three types of shape complementarity between polypeptides, desolvation between the polypeptides, and electrostatic interaction between the polypeptides. Since the structural complementarity is evaluated based on the above characteristics, the accuracy of evaluating the structural complementarity of the three-dimensional structure model in a conjugate of a plurality of polypeptides is improved.

  In the present invention, the above-described conjugate model evaluation apparatus acquires known binding participation information that defines amino acid residues involved in binding to other polypeptides among the amino acid residues of each polypeptide. A binding participation information acquisition unit; and a binding participation index generation unit that generates a binding participation index in the entire three-dimensional structure model of the conjugate based on the known binding participation information of the three-dimensional structure model of each polypeptide. The total suitability evaluation unit described above may further generate a comprehensive suitability index based on the binding participation index.

  According to this configuration, since the above-described comprehensive compatibility evaluation unit further evaluates the comprehensive compatibility based on the binding participation index, it is possible to effectively use known information, and a conjugate of a plurality of polypeptides. The accuracy of evaluating the conformity of the three-dimensional structure model is improved.

  Further, in the present invention, the conjugate model evaluation apparatus includes a model acquisition unit that acquires each of the three-dimensional structure models of a plurality of polypeptides, and a conjugate based on each of the three-dimensional structure models of the plurality of polypeptides. And a combined model generation unit that generates the three-dimensional structure model.

  According to this configuration, even when a three-dimensional structure model of each of a plurality of polypeptides is obtained, a three-dimensional structure model of a conjugate of these polypeptides is generated, so that a three-dimensional structure of a conjugate of a plurality of polypeptides can be obtained. The suitability of the structural model can be evaluated.

  Further, in the present invention, the conjugate model evaluation apparatus described above includes a sequence acquisition unit that acquires information that specifies each amino acid sequence of a plurality of polypeptides, and information that specifies each amino acid sequence of the plurality of polypeptides. And a single model generation unit for generating a three-dimensional structure model of each of the plurality of polypeptides.

  According to this configuration, even when information defining each amino acid sequence of a plurality of polypeptides is acquired, a plurality of polypeptides are generated by generating a three-dimensional structure model of each of the plurality of polypeptides from these amino acid sequences. The suitability of the three-dimensional structure model of the conjugate between peptides can be evaluated.

  Further, in the present invention, the total suitability evaluation unit described above normalizes each index of the three-dimensional structure model of the conjugate, and based on each normalized index, the general suitability index of the three-dimensional structure model of the conjugate May be generated.

  According to this configuration, since each index is normalized, it is possible to handle each index in the same dimension, and it is possible to generate a comprehensive suitability index by synthesizing each index.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings. In all the drawings, the same reference numerals are given to the same components, and the description will be omitted as appropriate.

<Embodiment 1>
FIG. 1 is a functional block diagram illustrating a configuration of a combined body model evaluation apparatus according to the first embodiment. The conjugate model evaluation apparatus 100 is an apparatus that evaluates a conjugate model of a plurality of polypeptides. For example, as described later in FIGS. 17 to 19, the conjugate model evaluation apparatus 100 includes a plurality of themes as shown in the theme of the prediction contest “CAPRI (Critical Assessment of Pedition of Interactions)” of the protein-protein docking structure. When a three-dimensional structure model of each polypeptide is provided, it is intended to be used for prediction of a three-dimensional structure model of a conjugate.

  That is, an object of the present invention is to perform a docking analysis by the conjugate model evaluation apparatus 100 by using a computer method for evaluating the three-dimensional structure model of the conjugate, and to accurately evaluate the three-dimensional model of the conjugate.

  When the combined body model is generated outside, the combined body model evaluation apparatus 100 includes a combined body model acquisition unit 102. The conjugate model acquisition unit 102 generates a three-dimensional structure of a plurality of conjugates generated by an arbitrary program based on the three-dimensional structure model (for example, the receptor three-dimensional structure model and the ligand three-dimensional structure model) of the plurality of polypeptides. A structural model (for example, a three-dimensional structure model of a receptor-ligand complex) is acquired from the outside. The three-dimensional structure model of the combined body acquired in this way is stored in the combined body model storage unit 104.

  On the other hand, the combined body model evaluation apparatus 100 is provided with a combined participation information acquisition unit 114 connected to an external database or the like. The binding involvement information acquisition unit 114 is known binding involvement information (for example, literature known information or known experiment) that defines amino acid residues involved in binding to other polypeptides among amino acid residues of each polypeptide. Data). The known binding participation information acquired in this way is stored in the binding participation information storage unit 116.

  The combined body model evaluation apparatus 100 is provided with a selection unit 140 including a docking prediction program such as ZDOCK. The selection unit 140 selects a three-dimensional structure model of a combined body that satisfies a predetermined criterion from a plurality of three-dimensional structure models of the combined body.

  The selection unit 140 includes a structural complementarity evaluation unit 106. As will be described later with reference to FIG. 4, the structural complementarity evaluation unit 106 generates a structural complementarity index based on the structural complementarity between the polypeptides in the three-dimensional structure model of the conjugate. The structural complementarity index is a score indicating the degree of structural complementarity between the polypeptides constituting the conjugate.

  More specifically, the structural complementarity evaluation unit 106 is based on the shape complementarity between the polypeptides, the desolvation between the polypeptides, and the electrostatic interaction between the polypeptides. Generate a structural complementarity indicator for the conjugate.

  For example, the structural complementarity evaluation unit 106 of the selection unit 140 may include an evaluation component of a docking prediction program such as ZDOCK. ZDOCK is a protein docking program based on protein shape complementation, desolvation, and electrostatic interaction, developed at Boston University. The URL is http: // zlab. bu. Available from edu / zdock /.

  ZDOCK is a component that generates a binding model of each protein based on protein shape complementarity, desolvation, electrostatic interaction, and compatibility of the generated binding model. A program including a desolvation and an evaluation component for evaluation based on electrostatic interaction.

  In ZDOCK, a protein is treated as a rigid body, the rotation angle of each molecule is controlled as an Euler angle, and FFT processing is performed. As described later in FIG. I do. The structural complementarity index corresponds to the rank generated by the evaluation component of ZDOCK.

  In addition, as will be described later with reference to FIG. 4, in the ZDOCK evaluation component, in addition to the shape complementarity, the binding structure is ranked by the structural complementarity index based on the electrostatic interaction energy and the ACE desolvation energy. . The structural complementarity index obtained in this way is stored in the structural complementarity index storage unit 108.

  The selection unit 140 is provided with a combined model selection unit 110. The conjugate model selection unit 110 selects a three-dimensional structure model of a conjugate whose structural complementarity index is equal to or greater than a threshold value from a plurality of three-dimensional structure models of the conjugate.

  For example, a three-dimensional structure model of a conjugate in which the structural complementarity index by the evaluation component of ZDOCK is greater than or equal to a predetermined value, or the structural complementarity index is within a predetermined number from the top is selected. As a more detailed example, a three-dimensional structure model (candidate complex formation state) of a conjugate whose structural complementarity index by ZDOCK is 2000 or less from the top may be selected. The three-dimensional structure model of the combined body selected in this way is stored in the selected combined body model storage unit 112.

  The combined body model evaluation apparatus 100 is provided with a conformity evaluation unit 142. As will be described later with reference to FIG. 2, the suitability evaluation unit 142 evaluates the suitability of the three-dimensional structure model of the selected combined body. The conformity evaluation unit 142 includes, for example, a three-dimensional structure prediction program called CQS formed by combining Verify 3D and Prosa 2003.

  The suitability evaluation unit 142 is provided with an environment suitability evaluation unit 118. As will be described later with reference to FIG. 6, the environmental compatibility evaluation unit 118 is based on the degree of peripheral polarity for each amino acid residue and the degree of solvent exposure of the side chain for each amino acid residue in the three-dimensional structure model of the selected conjugate. Generate an index of water compatibility of the entire three-dimensional model of the conjugate and an environmental compatibility index for the protein internal environment. The environmental suitability evaluation unit 118 includes, for example, a 3D structure evaluation program called Verify 3D. The environmental suitability index obtained in this way is stored in the environmental suitability index storage unit 120.

  The compatibility evaluation unit 142 is provided with a distance-dependent potential energy evaluation unit 122. The distance-dependent potential energy evaluation unit 122 is selected based on the distance-dependent potential energy for each amino acid residue pair in the three-dimensional structure model of the selected conjugate, as will be described later with reference to FIGS. A distance-dependent potential energy index for the entire three-dimensional structure model of the conjugate is generated. The distance-dependent potential energy evaluation unit 122 includes, for example, a three-dimensional structure evaluation program called Prosa 2003. The distance-dependent potential energy index thus obtained is stored in the distance-dependent potential energy index storage unit 124.

  In addition, the compatibility evaluation unit 142 is provided with a coupling participation index generation unit 126. As described later with reference to FIG. 11, the binding participation index generation unit 126 is based on the known binding participation information of the three-dimensional structure model of each polypeptide acquired by the above-described binding participation information acquisition unit 114. A binding participation index (such as the number of contacts between amino acid residues known to be involved in binding) in the entire three-dimensional structure model is generated. The coupling participation index obtained in this way is stored in the coupling participation index storage unit 128.

  In addition, the suitability evaluation unit 142 is provided with a comprehensive suitability evaluation unit 130. The comprehensive compatibility evaluation unit 130 includes an environmental compatibility index derived from the environmental compatibility evaluation unit 118, a distance dependent potential energy index derived from the distance dependent potential energy evaluation unit 122, a binding participation index derived from the coupling participation index generation unit 126, Alternatively, based on the structural complementarity index derived from the structural complementarity evaluation unit 106, an overall compatibility index of the three-dimensional structure model of the conjugate is generated. The normalization method and calculation method of each index for obtaining the comprehensive suitability index will be described later in detail. The comprehensive suitability index thus obtained is stored in the comprehensive suitability index storage unit 132.

  The combined body model evaluation apparatus 100 is provided with an output unit 134. The evaluation result (total compatibility index) by the suitability evaluation unit 142 is output to the outside via the output unit 134.

  FIG. 2 is a conceptual diagram for explaining a method for evaluating a three-dimensional structure model of a combined body in the first embodiment. As shown in FIG. 2, in the combined body model evaluation apparatus 100, for the combined model generated by the ZDOCK docking component, the 3D structure model of the combined body is selected based on the structural compatibility by the ZDOCK evaluation component. Then, indices such as environmental compatibility (index by Verify 3D) and distance-dependent potential energy (index by Prosa 2003) are evaluated for the entire three-dimensional structure model of the conjugate. Normally, Verify 3D and Prosa 2003 are used for evaluating the three-dimensional structure of a single polypeptide, but in this embodiment, it is used for evaluating the entire three-dimensional structure model of the conjugate.

  In this case, the illustrated binding region (the middle contact portion) between the left and right polypeptides is evaluated as a region corresponding to the interior of the polypeptide in the case of a single polypeptide. Therefore, the conjugate model evaluation apparatus 100 can accurately evaluate the conformity of the three-dimensional structure when the two left and right illustrated polypeptides are regarded as a single polypeptide.

  In this way, after selecting a three-dimensional structure model of a conjugate based on structural compatibility (index by ZDOCK, etc.), environmental compatibility (index by Verify 3D) and distance conventionally used only for evaluating a single polypeptide. Since an index such as dependent potential energy (an index according to Prosa 2003) is applied to the entire conjugate, the conjugate model evaluation apparatus 100 accurately determines the conformity of the three-dimensional structure model of the conjugate between a plurality of polypeptides. Can be evaluated well.

  FIG. 3 is a functional block diagram showing details of the structure of the structural complementarity evaluation unit in the first embodiment. FIG. 4 is a conceptual diagram for explaining an evaluation method by the structural complementarity evaluation unit in the first embodiment.

  The structural complementarity evaluation unit 106 is provided with a shape complementarity evaluation unit 202. As shown in FIG. 4, the shape complementarity evaluation unit 202 evaluates the complementarity of the unevenness of the surface of each polypeptide for the whole conjugate, and generates a shape complementarity index. The shape complementarity index is a score indicating the degree of complementarity of the surface irregularities of each polypeptide. For example, when using an evaluation component of ZDOCK, a binding site is predicted by handling a protein as a rigid body, controlling the rotation angle of each molecule as an Euler angle, and performing FFT processing. The shape complementarity index obtained in this way is stored in the shape complementarity index storage unit 204.

  The structural complementarity evaluation unit 106 is provided with a desolvation evaluation unit 206. In general, polarized species are solvated by a polar solvent such as water. When solvated, solvation energy is released and stabilized. Conversely, desolvation destabilizes.

  As shown in FIG. 4, the desolvation evaluation unit 206 evaluates the entire conjugate for desolvation that occurs in the binding region of the three-dimensional structure model of the conjugate when each polypeptide binds to each other. Generate a sum indicator. The desolvation index is a score indicating the magnitude of desolvation that occurs in the binding region of the three-dimensional structure model of the conjugate when each polypeptide binds. For example, when the ZDOCK evaluation component is used, the ACE desolvation energy is evaluated. The desolvation index obtained in this way is stored in the desolvation index storage unit 208.

  The structural complementarity evaluation unit 106 is provided with an electrostatic interaction evaluation unit 210. Electrostatic interaction is the interaction between the charges on the surface of each polypeptide. In the electrostatic interaction evaluation unit 210, the electrostatic interaction between the polypeptides is evaluated for the entire conjugate based on the electrostatic interaction (attraction-repulsive force) for each amino acid residue of the plurality of polypeptides. And an electrostatic interaction index is generated. The electrostatic interaction index is a score indicating the sign and magnitude of electrostatic interaction between each polypeptide. For example, when using the ZDOCK evaluation component, the electrostatic interaction energy between the polypeptides is also evaluated. The electrostatic interaction index thus obtained is stored in the electrostatic interaction index storage unit 212.

  The structural complementarity evaluation unit 106 is provided with an index synthesis unit 214. The index synthesizer 214 determines the structural complementarity of the conjugate based on the shape complementarity between the polypeptides, the desolvation between the polypeptides, and the electrostatic interaction between the polypeptides. Generate indicators. For example, the ZDOCK evaluation component evaluates the structural compatibility of the conjugate based on electrostatic interaction energy and ACE desolvation energy in addition to shape complementarity.

More specifically, when ZDOCK is used, the above-described shape complementarity index (S _SC ), desolvation index (S _DS ), and electrostatic interaction index (S _ELEC ), which are respectively normalized in advance. Are appropriately weighted and substituted into the formula S = αS _SC + S _DS + βS _ELEC to generate a structural complementarity index. In the above formula, α and β are predetermined constants for weighting.

  FIG. 5 is a functional block diagram showing details of the configuration of the environmental suitability evaluation unit in the first embodiment. FIG. 6 is a conceptual diagram for explaining an evaluation method by the environmental suitability evaluation unit in the first embodiment.

  The environmental suitability evaluation unit 118 is provided with a peripheral polarity evaluation unit 302. The peripheral polarity evaluation unit 302 evaluates the peripheral polarity for each amino acid residue in the three-dimensional structure model of the selected conjugate (corresponding to the Fraction Polar index on the right side of FIG. 6). The peripheral polarity degree generated in this way is stored in the peripheral polarity degree storage unit 304.

  The environmental suitability evaluation unit 118 is provided with a solvent exposure degree evaluation unit 306. The solvent exposure degree evaluation unit 306 evaluates the solvent exposure degree of the side chain for each amino acid residue in the three-dimensional structure model of the selected conjugate (inversely correlated with the index of the upper embedded region in FIG. 6). At this time, since the area of the embedded region and the degree of solvent exposure are inversely correlated, evaluating one is equivalent to evaluating the other. The solvent exposure degree thus generated is stored in the solvent exposure degree storage unit 308.

  The environmental suitability evaluation unit 118 is provided with a secondary structure evaluation unit 310. The secondary structure evaluation unit 310 evaluates the secondary structure (other structures such as α helix, β sheet, and loop) formed by each amino acid residue in the three-dimensional structure model of the selected conjugate. To do. The secondary structure type (any one of the three types) generated in this way is stored in the secondary structure storage unit 312.

  The environment suitability evaluation unit 118 is provided with an environment class evaluation unit 318 that classifies the environment class of the combined body into 18 levels. In addition to the above-mentioned peripheral polarity and solvent exposure, the environment class evaluation unit 318 further determines the water solubility of the entire three-dimensional structure model of the conjugate and the internal environment of the protein based on the secondary structure formed by the amino acid residue. Generate the environmental class index (environment suitability index) of the stage. The 18-stage environmental class indices generated in this way are stored in the environmental class storage unit 320.

  More specifically, when Verify 3D is used, the environmental class of residues in the three-dimensional structure of the conjugate is evaluated (determined) using the classification diagram of FIG. First, the solvent contact surface area (solvent exposure) is calculated for each residue of the three-dimensional structure model. Then, the difference from the solvent contact surface area of Gly-XGly peptide is defined as Area Buried (residue embedding degree).

  Then, the fraction covered with polar atoms (including the solvent) in the surface area of each residue in the three-dimensional structure model is defined as Fraction Polar (peripheral polarity). Next, the environmental class to which each residue (a) belongs (j) is determined from the classification diagram of FIG.

  In other words, amino acid residues are classified into 18 environmental classes based on the region where the side chains of amino acid residues are buried in protein (solvent exposure), the degree of polarity around the amino acid residues, and the secondary structure of the main chain. Classify into: Then, the score of the residue (environment suitability index) is calculated by the formula described later.

Here, the contents of the six-level classification symbols define the environment in which the residue is placed, and are broadly divided into Burried (B), Partially buried (P), and Exposed (E). Is as follows.
E: Environment in contact with solvent P1: Partially buried; Slightly polar environment P2: Partially buried; Polar environment B1: Buried; Hydrophobic environment B2: Buried; Slightly polar environment B3: buried; polar environment

  About these, about the three-dimensional structure registered into PDB (protein three-dimensional structure database), the frequency in each environment is calculated for every kind of residue. For example, large hydrophobic residues prefer B1, B2, B3, and hydrophilic residues prefer the E environment. However, polar residues such as glutamine (Q) can be taken with B3.

  For FIG. 6, the horizontal axis is the buried surface area of each side chain residue. E is A <40, P is 40 ≦ A ≦ 114, and B is 114 ≦ A (the unit is angstrom). The vertical axis represents the ratio of the surface surrounded by polar residues. B1 is f <0.45, B2 is 0.45 ≦ f <0.58, B3 is 0.58 ≦ f, P1 is f <0.67, and P2 is 0.67 ≦ f. (All units are angstroms.) Here, A indicates Area Buried, and f indicates Fraction Polar.

  The environmental suitability evaluation unit 118 is provided with an index conversion unit 322. In the index conversion unit 322, statistical data is collected and stored in advance for the appearance frequency of each amino acid in the three-dimensional structure of the polypeptide in the above-described 18-stage environmental class with a highly accurate crystal structure. For example, the 3D score table obtained as a result of aligning 16 types of proteins with known structures and proteins having homology thereto, which was published in Proteins (1991) by Luethy et al., Can be suitably used.

Then, the index conversion unit 322 compares the classification of each amino acid into the above-described 18-stage environmental class and the appearance frequency set in advance using the formula of S _aj = log (P _{a: j} / P _a ). An environmental compatibility index of the amino acid in the three-dimensional structure model is generated according to how much the predicted three-dimensional structure model of the conjugate conforms to the statistical value. In the above equation, S _aj is an environmental suitability index of residue a in environment j, P _{a: j} is a conditional probability of finding residue type a in environment j, and P _a is The total probability of observing residue a.

  In this case, the score is low if the appearance frequency is low in the PDB (protein database). That is, if the score is low, there is a high possibility that the three-dimensional structure model is wrong. For example, if a residue that is often in the Exposed environment is in the Buried environment in the three-dimensional structure model, there is a high possibility that the three-dimensional structure model is incorrect.

  The environmental suitability evaluation unit 118 is provided with an all-amino acid index synthesis unit 324. The total amino acid index synthesis unit 324 synthesizes the environmental compatibility index for each amino acid described above to generate an environmental compatibility index for all amino acids. The environmental suitability index obtained in this way is stored in the environmental suitability index storage unit 120.

  FIG. 7 is a functional block diagram showing details of the configuration of the distance-dependent potential energy evaluation unit in the first embodiment. 8 and 9 are conceptual diagrams for explaining an evaluation method by the distance-dependent potential energy evaluation unit in the first embodiment.

  The distance-dependent potential energy evaluation unit 122 is provided with a residue pair distance evaluation unit 402. The residue pair distance evaluation unit 402 examines the position of the secondary structural element of the α helix and β strand in the three-dimensional structure model and the three-dimensional structure model for each amino acid residue in the three-dimensional structure model of the selected conjugate. The distance of the residue pair (Cα-Cα, Cβ-Cβ) of the secondary structural element of α-helix and β-strand is evaluated. The residue pair distances obtained in this way are stored in the residue pair distance storage unit 404.

  The distance-dependent potential energy evaluation unit 122 includes a residue pair distance-dependent potential energy evaluation unit 406. In the residue pair distance-dependent potential energy evaluation unit 406, statistical data of distance-dependent potential energy of residue pairs (Cα-Cα, Cβ-Cβ) obtained in advance from the crystal structure of a polypeptide whose structure is already known is stored in PDB ( Collected from the protein 3D structure database) and stored. Actually, contacts between amino acid residues are comprehensively analyzed, and a list of energies associated with these contacts is created. This list may be stored.

  The residue pair distance-dependent potential energy evaluation unit 406 compares the distance of the residue pair (Cα-Cα, Cβ-Cβ) in the three-dimensional structure model of the selected conjugate with the statistical data, The distance-dependent potential energy of each residue pair (Cα-Cα, Cβ-Cβ) is evaluated by the equation E (r) = − kTln [f (r)]. In the above equation, E (r) is the residue pair distance-dependent potential energy, f (r) is the probability density function of the distance r, k is the Boltzmann constant, and T is Absolute temperature (K). The distance-dependent potential energy index of the residue pair thus obtained is stored in the residue pair distance-dependent potential energy index storage unit 408.

  The distance-dependent potential energy evaluation unit 122 is provided with an all-amino acid index synthesis unit 410. The index synthesizer 410 synthesizes the distance-dependent potential energy of each residue pair (Cα-Cα, Cβ-Cβ) for the residue pairs (Cα-Cα, Cβ-Cβ) of all amino acid residues and combines them. A distance-dependent potential energy index is generated for the whole body structure model. The distance-dependent potential energy thus obtained is stored in the distance-dependent potential energy index storage unit 124.

  Thus, in the distance-dependent potential energy evaluation unit 122, the (Cα-Cα) distance-dependent potential energy of the rubisco protein has a correct three-dimensional structure, as shown in FIG. 8 cited from a paper published by Shippl and published in 1993. In the model, when the horizontal axis is the amino acid number and the vertical axis is the Z-value (energy density of the distance-dependent potential energy), the value is low as shown in the left graph, and in the wrong three-dimensional structure model, as shown on the right side. High value.

  Further, in the distance-dependent potential energy evaluation unit 122, as shown in FIG. 9 quoted from a paper published by Shippl, published in 1990, the distribution of lysozyme (PDB code 11z3) derived from polyprotein is represented by a Z-value ( The energy distribution of the distance-dependent potential energy), and the vertical axis represents the number of randomly generated three-dimensional structure models indicates a normal distribution. Note that the total number of randomly generated three-dimensional structure models of lysozyme is 50000. The down arrow indicates a natural (correct) conformational model protein. Thus, a natural (correct) three-dimensional model protein has a low Z-value (energy density of distance-dependent potential energy).

  FIG. 10 is a functional block diagram illustrating details of the configuration of the binding participation index evaluation unit in the first embodiment. FIG. 11 is a conceptual diagram for explaining an evaluation method performed by the joint participation index evaluation unit in the first embodiment.

  The binding participation index evaluation unit 126 includes a binding participation amino acid specifying unit 502. The binding-participating amino acid specifying unit 502 calculates amino acid residues involved in binding between polypeptides in the selected three-dimensional structure model from the three-dimensional structure model of the selected conjugate and known binding participation information. Identify. Information defining the amino acid residues involved in the binding specified in this way is stored in the binding participating amino acid storage unit 504.

  The above-described known binding participation information (biological data) may be, for example, information obtained by annotating a part important for complex binding (generation of a conjugate) in advance from literature or sequence analysis.

  Moreover, the above-mentioned known binding participation information may be information derived from PDB: Protein Data Bank, for example. The PDB includes three-dimensional structure data by X-ray crystallography and NMR, three-dimensional coordinates of each atom, secondary structure: α helix, β sheet, other loops, and other information.

  PDB is a consortium centered on Rutgers University and the URL is http: // www. rcsb. org / pdb /. In addition, the mirror site in Japan and original XML conversion are also performed, and the URL is http: // pdb. protein. osaka-u. ac. jp / pdb / and http: // pdbj. protein. osaka-u. ac. jp /. Alternatively, a keyword search on the genome net can be performed, and the URL is http: // www. genome. ad. jp / dbget-bin / www_bfind? pdb.

  The binding participation index evaluation unit 126 is provided with a binding participation amino acid counting unit 506. As shown in FIG. 11, the binding participating amino acid counting unit 506 counts the number of amino acid residues involved in the identified binding in the three-dimensional structure model of the conjugate.

  More specifically, after the above annotation, the sum of the number of contacts (DIMPLOT) in the entire complex (conjugate) of the annotated residues in the complex candidate structure (conjugate three-dimensional structure model) is scored. The binding participation amino acid count value thus counted is handled as a binding participation index as it is and stored in the binding participation index storage unit 128.

  FIG. 12 is a functional block diagram showing details of the configuration of the comprehensive compatibility evaluation unit in the first embodiment. FIG. 13 is a conceptual diagram for explaining normalization in the comprehensive compatibility evaluation unit in the first embodiment.

  The comprehensive suitability evaluation unit 130 includes a baseline storage unit 604 as shown in FIG. The baseline storage unit 604 stores a baseline obtained by drawing a regression line in advance for an environmental compatibility index of a polypeptide having a dummy random amino acid sequence. In FIG. 13A, the horizontal axis is the protein length, and the vertical axis is the environmental compatibility index.

Next, the normalization unit 606 normalizes the environmental suitability index using the baseline. More specifically, it is normalized (non-dimensionalized) by the following series of equations. The normalized environmental suitability index is stored in the normalized environment suitability index storage unit 608.
Q _{verify 3D} = (S _quality -S _low ) / (S _high -S _low )
S _quality = ΣS _{i, j}
S _high = exp (−0.83 + 1.008 × ln (L))
S _low = 0.45 × S _high
In the above formula, Q _{verify 3D} is an environment suitability index by Verify 3D normalized by the protein length, S _quality is an actually measured environment suitability index, and S _high is the protein length L. Is an ideal value of the environmental compatibility index, and S _low is a threshold value of the environmental compatibility index determined to be appropriate, and L is the protein length (number of amino acid residues).

  Further, as shown in FIG. 13B, the comprehensive suitability evaluation unit 130 includes a baseline generation unit 610 that generates a baseline for the distance-dependent potential energy index. In FIG. 13B, in the graph in which the horizontal axis is the protein length and the vertical axis is the Z-value, the distance-dependent potential energy index having the largest Z-value is represented by the regression line of the distance-dependent potential energy index. Baselines are generated by drawing parallel lines. The baseline generated in this way is stored in the baseline storage unit 612.

Next, in the normalization unit 614, the distance-dependent potential energy index is normalized using the baseline. More specifically, it is normalized (non-dimensionalized) by the following series of equations. The distance-dependent potential energy index thus normalized is stored in the normalized distance-dependent potential energy index storage unit 616.
Q _prosa = (ZS−ZS _low ) / (ZS _high −ZS _low )
ZS _high = −6.67−0.0141L
ZS _low = −3.32−0.0141L
In the above formula, Q _prosa is a Z-value (distance-dependent potential energy index) by Prosa normalized by the protein length, and S _high is an ideal value of the Z-value when the protein length is L. ZS is the Z-value of the (C _β -C _β ) binding energy of the target three-dimensional structure model, S _low is the threshold value of the Z-value judged to be appropriate, and L is the protein Long (number of amino acid residues).

  Further, the comprehensive suitability evaluation unit 130 generates, for example, CQS (combined q-score) by the following series of formulas based on the normalized environmental suitability index and the normalized distance-dependent potential energy index. A CQS evaluation unit 618 is provided. CQS is an evaluation value for protein three-dimensional structure prediction developed at the Center for Bioinformatics Research (CBRC) of the National Institute of Advanced Industrial Science and Technology (AIST). That is, CQS is an index indicating the conformity of the configuration of amino acid residues contained in a protein. The CQS obtained in this way is stored in the CQS storage unit 620.

The following formula is established for the value of CQS.
CQS = sign (Q _{verify 3D} , Q _prosa ) Q _{verify 3D} Q _prosa

For the sign function, the following equation is established.
First, when Q _{verify 3D} <0 and Q _prosa <0, the following equation holds.
sign (Q _{verify 3D} , Q _prosa ) = − 1
On the other hand, when Q _{verify 3D} ≧ 0 or Q _prosa ≧ 0, the following equation holds.
sign (Q _{verify 3D} , Q _prosa ) = 1

In the above formula, Q _{verify 3D} is an environmental suitability index by Verify 3D normalized by protein length. Q _prosa is a Z-value (distance-dependent potential energy index) by Prosa normalized by the protein length.

  Further, the overall compatibility evaluation unit 130 includes a normalization unit 622 that normalizes (non-dimensionalizes) the CQS in consideration of the standard deviation. The normalized CQS is stored in the normalized CQS storage unit 624.

  On the other hand, the above-described combination participation index is also normalized (non-dimensionalized) by the normalizing unit 626 in consideration of the standard deviation. The normalized binding participation index thus stored is stored in the normalized binding participation index storage unit 628. Further, the above-described structural complementarity index is also normalized (non-dimensionalized) by the normalizing unit 630 in consideration of the standard deviation. The normalized structure complementarity index is stored in the normalized structure complementation finger storage unit 632.

The comprehensive suitability evaluation unit 130 includes an index composition unit 634 that synthesizes each index based on each index normalized in consideration of the above-described standard deviation and generates a comprehensive suitability index. At this time, the index synthesis unit 634 synthesizes each index according to the following formula. The comprehensive suitability index synthesized in this way is stored in the comprehensive suitability index storage unit 132.
S _core = ZS ^CQS + ZS ^ZDOCK + ZS ^Contact
In the above equation, S _core is a comprehensive fitness index, ZS ^CQS is a normalized CQS, ZS ^ZDOCK is a normalized ZDOCK score, and ZS ^Contact is normalized. It is a binding participation index.

  Thus, CQS, which is usually a protein (monomer) structure prediction evaluation program, is calculated for each complex candidate (stereostructure model of each conjugate), and based on these, each complex candidate is calculated. In order to determine the final conjugate model from the overall score of CQS and other complex evaluation values (indexes), it is possible to accurately determine the compatibility of each complex candidate between multiple polypeptides. It is possible to evaluate and obtain a conjugate model with high compatibility.

Hereinafter, the operation of the combined body model evaluation apparatus 100 will be described.
FIG. 14 is a flowchart for explaining the operation of the combined body model evaluation apparatus according to the first embodiment. When the combined body model evaluation apparatus 100 starts a series of operations, the combined body model acquisition unit 102 acquires a three-dimensional structure model of a combined body generated outside (S102).

  Next, structural complementarity evaluation is performed by the structural complementarity evaluation unit 106 on the acquired three-dimensional structure model of the combined body (S104). Based on the obtained structural complementarity index, the conjugate model selection unit 110 selects the three-dimensional structure model of the conjugate (S106).

  Further, the three-dimensional structure model of the selected combined body is evaluated for environmental compatibility by the environmental compatibility evaluation unit 118 (S108). On the other hand, the distance-dependent potential energy of the three-dimensional structure model of the selected conjugate is evaluated by the distance-dependent potential energy evaluation unit 122 (S110). The three-dimensional structure model of the selected conjugate is evaluated for the binding participation index by the binding participation index generation unit 126 (S112).

  Based on each of these indices, the comprehensive suitability evaluation unit 130 evaluates the comprehensive suitability of the three-dimensional structure model of the selected conjugate (S114). Subsequently, the comprehensive suitability index is output to the outside by the output unit 134 (S116), and the series of operations ends.

Hereinafter, the operation and effect of the combined body model evaluation apparatus 100 according to the first embodiment will be described.
FIG. 15 is a conceptual diagram for explaining a CQS calculation method in the combined body model evaluation apparatus according to the first embodiment. FIG. 16 is a graph showing the distribution of CQS when calculating the CQS of each of a number of polypeptides. Each polypeptide used here has a known three-dimensional structure by crystal structure analysis or the like, and should have a natural three-dimensional structure.

  As described above, when CQS is calculated for a large number of each polypeptide by the calculation method shown in FIG. 15 and distribution is obtained, the CQS values of some of the polypeptides become negative values. The horizontal axis in FIG. 15 is the CQS value, and the vertical axis is the number of each polypeptide having the CQS value. Also, the SCOP of the CQS value of each of the multiple polypeptides is 1.65-4. %Met. Thus, since the value of CQS of each polypeptide which should have a natural three-dimensional structure became negative, the present inventors sought the cause.

  As a result of the inventor's research, the cause of the negative CQS value of some of the polypeptides is that each polypeptide is naturally associated with other polypeptides and the like. Since the CQS of the peptide was calculated, the amino acid residues that should originally be in the binding region (inside the conjugate) were calculated as existing on the surface of each polypeptide, so that the CQS of some of each polypeptide The cause was assumed to be a negative value.

  Therefore, the present inventor made the whole conjugate as one polypeptide in the state of conjugates that are bound to other polypeptides, etc., for each polypeptide having a negative CQS value. When the CQS was calculated by handling it, the CQS value became a positive value.

  With this background, the inventor evaluated CQS (combination of Verify 3D and Prosa 2003), which is usually used for evaluating the three-dimensional structure of a single polypeptide, for the whole three-dimensional structure model of the conjugate, and based on these. Thus, it was conceived that the suitability of the three-dimensional structure model of a conjugate of a plurality of polypeptides can be evaluated with high accuracy by evaluating the suitability of the three-dimensional model of the conjugate.

  That is, the present inventor applied CQS (combined q-score) to the evaluation of the predicted three-dimensional structure model of the conjugate and used it to rank the three-dimensional model of the conjugate. Furthermore, the present inventor decided to configure this CQS as an index obtained by two major protein structure evaluation programs, Verify 3D and Prosa 2003.

  That is, according to the conjugate model evaluation apparatus 100 according to the present embodiment, the environmental compatibility and the distance-dependent potential energy normally used for evaluating the three-dimensional structure of a single polypeptide are evaluated for the entire three-dimensional structure model of the conjugate. In addition, since the suitability of the three-dimensional structure model of the conjugate is evaluated based on these, the suitability of the three-dimensional structure model of the conjugate of a plurality of polypeptides can be accurately evaluated.

  In addition, according to the conjugate model evaluation apparatus 100 according to the present embodiment, in order to select a three-dimensional structure model of a conjugate whose structural complementarity is equal to or higher than a predetermined level based on the structural complementarity between the polypeptides. Then, the computational burden in the subsequent evaluation of the suitability of the conformation model of the conjugate is reduced, and the suitability of the conformation model of the conjugate between a plurality of polypeptides can be efficiently evaluated.

  Moreover, according to the conjugate model evaluation apparatus 100 according to the present embodiment, in addition to the environmental compatibility and the distance-dependent potential energy described above, structural complementarity can be further evaluated. While maintaining the accuracy of evaluating the conformity of the three-dimensional structure model of the combined body, the calculation burden can be reduced and the evaluation can be efficiently performed as described above.

  Further, according to the conjugate model evaluation apparatus 100 according to the present embodiment, the structural complementarity evaluation unit 106 includes a shape complementarity evaluation unit between polypeptides, a desolvation between each polypeptide, and each polymorphism. Since ZDOCK that evaluates structural complementarity based on the three types of properties of electrostatic interaction between peptides is used, the accuracy of structural complementarity evaluation of a three-dimensional structure model in a conjugate of a plurality of polypeptides is improved.

  In addition, according to the combined body model evaluation apparatus 100 according to the present embodiment, the above-described comprehensive compatibility evaluation unit 130 includes, in addition to the above-described indexes, a binding participation index (from the PDB via the Internet or the like) ( Since comprehensive compatibility is evaluated based on (Biological Data), known information can be used effectively, and the accuracy of evaluating the conformity of a three-dimensional structure model of a conjugate of a plurality of polypeptides is improved.

  Moreover, according to the conjugate model evaluation apparatus 100 according to the present embodiment, in addition to the environmental compatibility and the distance-dependent potential energy described above, the conjugate three-dimensional structure is further based on the secondary structure formed by amino acid residues. Since the environmental compatibility index for the water solubility of the entire structural model and the internal environment of the protein is generated, the environmental compatibility can be evaluated with higher accuracy.

  Further, according to the combined body model evaluation apparatus 100 according to the present embodiment, each index is normalized by the plurality of normalization units 606, 614, 622, 626, and 630 in the overall suitability evaluation unit 130 described above. Therefore, based on an equivalent standard for each index, each index can be synthesized to generate a comprehensive suitability index.

  FIG. 17 is a conceptual diagram for explaining the history of CAPRI. FIG. 18 is a conceptual diagram for explaining a CAPRI question theme. Further, FIG. 19 is a conceptual diagram for explaining a contest examination result applied for CAPRI using the combined body model evaluation apparatus according to the first embodiment.

  CAPRI is an abbreviation for Critical Assessment of Prediction of Interactions, and is a (protein-protein docking) contest that predicts the complex state (atomic coordinates) of two proteins with known structures. Each team can post up to 10 models and is evaluated with High, Acceptable, Incorrect, Classes-indirect.

  As shown in FIG. 17, the 6th round was held recently in January-February 2005 and is currently in the middle of the 7th round (the results of the 7th round contest have not yet been released). ). Further, as shown in FIG. 18, the question theme is set as a monomer of disjoint receptor protein and ligand protein. The contributor is to answer this question as a three-dimensional model of the receptor protein-ligand protein conjugate.

  When the CBRC team to which the present inventor applied was applied to one of the 7th round themes (Target 21) using the combined model evaluation device 100, the contest examination result was 37 prediction teams as shown in FIG. The 337 structure was submitted, but two of the 10 structures predicted by the CBRC team were highly evaluated as “Acceptable”. In the upper right of FIG. 19, the ratio of each evaluation result is shown as a graph. As a result of evaluating the 3337 structure, there was no structure corresponding to “High”. From this graph, it can be seen that the accuracy of the evaluation result using the combined body model evaluation apparatus 100 is high.

  One of the structures (CBRC (model 8)) predicted by the CBRC team and highly evaluated as “Acceptable” is shown on the right side at the bottom of FIG. In addition, on the left side of the lower part of FIG. 19, the answer of the seventh round (Native: 1ZHl) is shown. That is, in the lower part of FIG. 19, the CBRC prediction result (model 8) of Target 21 (Orc1 / Sir1 conjugate) is compared with the natural structure. In either case, the arrangement of Sir (the darker protein) after comparison of the structure with Orc (the thinner protein) is compared.

  That is, although it is repeated, according to the conjugate model evaluation apparatus 100 according to the present embodiment, as can be seen from the results of FIGS. 17 to 19, the structural complementarity (index of ZDOCK) of each polypeptide is determined. Based on this, a three-dimensional structure model of a conjugate having a structural complementarity equal to or higher than a predetermined level is selected, and then CQS (a combination of Verify 3D and Prosa 2003), which is usually used for evaluating the three-dimensional structure of a single polypeptide. Evaluate the overall conformation model of the conjugate and evaluate the suitability of the conformation model of the conjugate based on these to accurately evaluate the conformity of the conformation model of the conjugate between multiple polypeptides. can do.

<Embodiment 2>
In the second embodiment, an embodiment in which the combined model obtaining unit 102 of the combined model evaluation apparatus 100 according to the first embodiment is replaced with a model generating unit 800 will be described. Note that the configuration of the second embodiment is the same as the configuration of the first embodiment except when specifically mentioned.

  FIG. 20 is a functional block diagram illustrating details of the configuration of the model generation unit of the combined body model evaluation apparatus according to the second embodiment. The model generation unit 800 is provided with a first model acquisition unit 802 that acquires a three-dimensional structure model of each first polypeptide (receptor protein). The three-dimensional structure model of the first polypeptide thus obtained is stored in the first model storage unit 708.

  On the other hand, the model generation unit 800 is provided with a second model acquisition unit 804 that acquires each three-dimensional structure model of the second polypeptide (ligand protein). The three-dimensional structure model of the second polypeptide thus obtained is stored in the second model storage unit 716.

  Based on the three-dimensional structure model of each of the first polypeptides thus obtained and the three-dimensional structure model of each of the second polypeptides, the conjugate model generation unit 718 generates a conjugate of the first polypeptide and the second polypeptide ( A three-dimensional model of the receptor-ligand conjugate) is generated. The three-dimensional structure model of the combined body thus obtained is stored in the combined body model storage unit 104. For example, as the combined model generation unit 718, the above-described ZDOCK program can be suitably used.

  Hereinafter, the function and effect of the second embodiment will be described. Note that the effects of the second embodiment are the same as the effects of the first embodiment except when specifically mentioned.

  According to the second embodiment, even when a three-dimensional structure model of each of a plurality of polypeptides is acquired, the conjugate model generation unit 718 uses a ZDOCK docking component or the like to generate a conjugate of a plurality of polypeptides. A three-dimensional structure model can be generated. For this reason, also in Embodiment 2, similarly to the case of Embodiment 1, the conformity of the three-dimensional structure model of the conjugate | bonded_body of several polypeptides can be evaluated.

<Embodiment 3>
In the third embodiment, an embodiment in which the combined body model acquisition unit 102 of the combined body model evaluation apparatus 100 according to the first embodiment is replaced with a model generation unit 700 will be described. Note that the configuration of the third embodiment is the same as the configuration of the first embodiment except when specifically mentioned.

  FIG. 21 is a functional block diagram illustrating details of the configuration of the model generation unit of the combined body model evaluation apparatus according to the third embodiment. The model generation unit 700 is provided with a first sequence acquisition unit 702 that acquires information defining the amino acid sequence of each first polypeptide (receptor protein). The amino acid sequence of the first polypeptide thus obtained is stored in the first sequence storage unit 704.

  The model generation unit 700 is provided with a first model generation unit 706 that generates each three-dimensional structure model of the first polypeptide based on information defining the amino acid sequence of the first polypeptide. Each three-dimensional structure model of the first polypeptide thus obtained is stored in the first model storage unit 708.

  For example, as the first model generation unit 706, a known program called MODELLER can be suitably used. In addition, it is desirable to confirm the suitability of each three-dimensional structure model of the first polypeptide using the above-described CQS program.

  When the model generation unit 700 acquires information defining each amino acid sequence of the second polypeptide (ligand protein) by the second sequence acquisition unit 710, the model generation unit 700 stores the information in the second sequence storage unit 712. Similarly to the above, the second model generation unit 714 generates each three-dimensional structure model of the second polypeptide and stores it in the second model storage unit 716. The description similar to that for the first polypeptide will not be repeated.

  Based on the three-dimensional structure model of each of the first polypeptides thus obtained and the three-dimensional structure model of each of the second polypeptides, the conjugate model generation unit 718 generates a conjugate of the first polypeptide and the second polypeptide ( A three-dimensional model of the receptor-ligand conjugate) is generated. The three-dimensional structure model of the combined body thus obtained is stored in the combined body model storage unit 104. For example, as the combined model generation unit 718, the docking component of the above-described ZDOCK program can be suitably used.

  Hereinafter, the function and effect of the third embodiment will be described. Note that the effects of the third embodiment are the same as the effects of the first embodiment except when specifically mentioned.

  According to the third embodiment, even when information defining the amino acid sequences of each of the plurality of polypeptides is acquired, the first model generation unit 706 and the second model generation unit 714 can obtain the three-dimensional data of each of the plurality of polypeptides. A structural model can be generated. The conjugate model generation unit 718 can generate a three-dimensional structure model of a conjugate of the plurality of polypeptides based on the three-dimensional structure model of each of the plurality of polypeptides. For this reason, also in Embodiment 3, similarly to the case of Embodiment 1, the conformity of the three-dimensional structure model of the conjugate | bonded_body of several polypeptides can be evaluated.

<Embodiment 4>
FIG. 22 is a functional block diagram illustrating an outline of the configuration of the combined model evaluation device according to the fourth embodiment. The conjugate model evaluation apparatus 400 according to the fourth embodiment is the conjugate model according to the first embodiment in that the structural complementarity evaluation unit 106 and the structural complementarity index storage unit 108 are provided in the suitability evaluation unit 142. Different from the evaluation device 100. The combined body model evaluation apparatus 400 is different from the combined body model evaluation apparatus 100 in that the selection unit 140 is not provided. The configuration of the fourth embodiment is the same as the configuration of the first embodiment except when specifically mentioned.

  FIG. 23 is a flowchart for explaining the operation of the combined body model evaluation apparatus according to the fourth embodiment. First, when the combined body model evaluation apparatus 400 starts a series of operations, the combined body model acquisition unit 102 acquires a 3D structure model of a combined body generated externally (S202).

  At this time, the conjugate model evaluation apparatus 400 does not select the three-dimensional structure model of the conjugate having a high ZDOCK score by using the ZDOCK evaluation component for the three-dimensional structure model of the conjugate. 100 is different.

  Next, the environmental suitability evaluation unit 118 evaluates the environmental suitability of the acquired three-dimensional structure model of the combined body (S204). On the other hand, the distance-dependent potential energy of the acquired three-dimensional structure model of the combined body is evaluated by the distance-dependent potential energy evaluation unit 122 (S206).

  Further, the structural complementarity evaluation unit 106 evaluates the structural complementarity of the acquired three-dimensional structure model of the combined body (S208). Furthermore, the binding participation index is evaluated by the binding participation index generation unit of the acquired three-dimensional structure model of the combined body (S210).

  Then, based on each of these indices, the total suitability evaluation unit 130 evaluates the total suitability of the three-dimensional structure model of the selected conjugate (S212). Subsequently, the comprehensive suitability index is output to the outside by the output unit 134 (S214), and the series of operations ends.

  Hereinafter, the function and effect of the fourth embodiment will be described. Except in particular cases, the operational effects of the fourth embodiment are the same as the operational effects of the first embodiment.

  According to the conjugate model evaluation apparatus 400 according to the fourth embodiment, Verify 3D and Prosa 2003, which are usually used for evaluating the three-dimensional structure of a single polypeptide, are evaluated for the whole three-dimensional structure model of the conjugate. By evaluating the score of the ZDOCK evaluation component between polypeptides and evaluating the conformity of the three-dimensional structure model of the conjugate based on these scores, the conformity of the three-dimensional structure model of the conjugate between multiple polypeptides is accurately determined Can be evaluated well.

  Further, according to the conjugate model evaluation apparatus 400 according to the fourth embodiment, the conjugate structure having a high ZDOCK score is obtained by using the ZDOCK evaluation component to convert the three-dimensional structure model of the conjugate before performing the processing by Verify 3D and Prosa 2003. Therefore, it is possible to evaluate the overall suitability of all of the obtained binding models, and to evaluate the conformity assessment accuracy of the conformation model of conjugates of multiple polypeptides. Can be improved.

  As mentioned above, although embodiment of this invention was described with reference to drawings, these are the illustrations of this invention, Various structures other than the above are also employable.

  For example, in the above embodiment, the protein-protein docking program is ZDOCK, but there is no particular limitation, and any other program can be suitably used as long as it is a program that evaluates shape complementarity.

  In the above embodiment, the environment class evaluation unit 318 is configured to have 18 levels of environment classes, but the present invention is not particularly limited. For example, the environment class evaluation unit 318 has six levels of environmental class indices (environment suitability indices) for the water solubility of the entire three-dimensional structure model of the conjugate and the internal environment of the protein based on the above-described peripheral polarity and solvent exposure. May be generated.

  In the above embodiment, the baseline of the environmental compatibility index is generated in advance using a dummy protein and stored in the baseline storage unit 604, and the baseline of the distance-dependent potential energy index is generated as a baseline. Although it is generated by the part 610, it is not intended to be particularly limited.

  Conversely, a baseline for an environmental suitability index may be generated by the baseline generation unit, and a baseline for a distance-dependent potential energy index may be generated in advance using a dummy protein and stored in the baseline storage unit. Good. In addition, the baselines of the environmental compatibility index and the distance-dependent potential energy index may be generated using a dummy protein and stored in the baseline storage unit. Alternatively, both the baseline of the environmental suitability index and the distance-dependent potential energy index may be generated by the baseline generation unit.

  As described above, the conjugate model evaluation apparatus according to the present invention has an effect that the conformity of a three-dimensional structure model of a conjugate of a plurality of polypeptides can be accurately evaluated. It is useful as a conjugate model evaluation apparatus, a conjugate model evaluation method, a conjugate model evaluation program, etc.

FIG. 3 is a functional block diagram illustrating an outline of a configuration of a combined body model evaluation apparatus according to the first embodiment. 3 is a conceptual diagram for explaining a method for evaluating a three-dimensional structure model of a combined body in Embodiment 1. FIG. 3 is a functional block diagram illustrating details of a configuration of a structural complementarity evaluation unit according to Embodiment 1. FIG. 6 is a conceptual diagram for explaining an evaluation method by a structural complementarity evaluation unit in Embodiment 1. FIG. 3 is a functional block diagram illustrating details of a configuration of an environmental suitability evaluation unit in Embodiment 1. FIG. It is a conceptual diagram for demonstrating the evaluation method by the environmental suitability evaluation part in Embodiment 1. FIG. 3 is a functional block diagram illustrating details of a configuration of a distance-dependent potential energy evaluation unit according to Embodiment 1. FIG. It is a figure quoted from a paper published in 1993 by Shippl. It is a figure quoted from a paper published in 1990 by Shippl. 4 is a functional block diagram illustrating details of a configuration of a binding participation index evaluation unit in Embodiment 1. FIG. FIG. 5 is a conceptual diagram for explaining an evaluation method by a joint participation index evaluation unit in the first embodiment. FIG. 3 is a functional block diagram illustrating details of a configuration of an overall compatibility evaluation unit in the first embodiment. 6 is a conceptual diagram for explaining normalization in a comprehensive suitability evaluation unit in Embodiment 1. FIG. 6 is a flowchart for explaining an operation of the combined body model evaluation apparatus according to the first embodiment. It is a conceptual diagram for demonstrating the calculation method of CQS in the conjugate | bonded_body model evaluation apparatus which concerns on Embodiment 1. FIG. It is a graph which shows distribution of CQS when calculating CQS of many each polypeptide. It is a conceptual diagram for demonstrating the history of CAPRI. It is a conceptual diagram for demonstrating the CAPRI question theme. It is a conceptual diagram for demonstrating the contest examination result applied to CAPRI using the conjugate | bonded_body model evaluation apparatus which concerns on Embodiment 1. FIG. It is a functional block diagram which shows the detail of a structure of the model production | generation part of the conjugate | bonded_body model evaluation apparatus which concerns on Embodiment 2. FIG. It is a functional block diagram which shows the detail of a structure of the model production | generation part of the conjugate | bonded_body model evaluation apparatus which concerns on Embodiment 3. FIG. It is a functional block diagram which shows the outline | summary of a structure of the conjugate | bonded_body model evaluation apparatus which concerns on Embodiment 4. FIG. 10 is a flowchart for explaining an operation of the combined body model evaluation apparatus according to the fourth embodiment.

Explanation of symbols

DESCRIPTION OF SYMBOLS 100 Conjugate model evaluation apparatus 102 Conjugate model acquisition part 104 Conjugate model memory | storage part 106 Structural complementarity evaluation part 108 Structural complementarity index memory | storage part 110 Conjugation model selection part 112 Selective conjugate model memory | storage part 114 Binding participation information acquisition part 116 Binding Involvement Information Storage Unit 118 Environmental Suitability Evaluation Unit 120 Environmental Suitability Index Storage Unit 122 Distance Dependent Potential Energy Evaluation Unit 124 Distance Dependent Potential Energy Index Storage Unit 126 Binding Involvement Index Generation Unit 128 Binding Involvement Index Storage Unit 130 Conformity evaluation unit 132 Total compatibility index storage unit 134 Output unit 140 Selection unit 142 Conformity evaluation unit 202 Shape complementarity evaluation unit 204 Shape complementarity index storage unit 206 Desolvation evaluation unit 208 Desolvation index storage unit 210 Static Electric interaction evaluation unit 212 Electrostatic interaction index storage unit 21 Index synthesis unit 302 Peripheral polarity evaluation unit 304 Peripheral polarity storage unit 306 Solvent exposure evaluation unit 308 Solvent exposure storage unit 310 Secondary structure evaluation unit 312 Secondary structure storage unit 318 Environmental class evaluation unit 320 Environmental class storage unit 322 Index conversion unit 324 Total amino acid index synthesis unit 402 Residue pair distance evaluation unit 404 Residue pair distance storage unit 406 Residue pair distance dependent potential energy evaluation unit 408 Residue pair distance dependent potential energy index storage unit 410 Total amino acid index Synthesis unit 502 Binding-related amino acid identification unit 504 Binding-related amino acid storage unit 506 Binding-related amino acid count unit 604 Baseline storage unit 606 Normalization unit 608 Normalized environment suitability index storage unit 610 Baseline generation unit 612 Baseline storage unit 614 Normal 616 Normalization distance dependent type Temporal energy index storage unit 618 CQS evaluation unit 620 CQS storage unit 622 Normalization unit 624 Normalization CQS storage unit 626 Normalization unit 628 Normalization binding participation index storage unit 630 Normalization unit 632 Normalized structure complementation finger storage unit 634 Index Synthesis unit 700 Model generation unit 702 First sequence acquisition unit 704 First sequence storage unit 706 Second model generation unit 708 Second model storage unit 710 Second sequence acquisition unit 712 Second sequence storage unit 714 Second model generation unit 716 First Two model storage unit 718 Combined model generation unit 800 Model generation unit 802 First model acquisition unit 804 Second model acquisition unit

Claims (16)

A conjugate model evaluation apparatus for evaluating a conjugate model of a plurality of polypeptides,
A conjugate model acquisition unit that acquires a three-dimensional structure model of the conjugate, which is generated based on the three-dimensional structure model of each of the plurality of polypeptides;
Based on the peripheral polarity for each amino acid residue in the three-dimensional structure model of the conjugate and the degree of solvent exposure of the side chain for each amino acid residue, the water solubility of the whole three-dimensional model of the conjugate and the environment for the internal environment of the protein An environmental suitability assessment unit that generates a suitability index;
A distance-dependent potential energy evaluation unit that generates a distance-dependent potential energy index for the entire three-dimensional structure model of the conjugate based on the distance-dependent potential energy of each amino acid residue pair in the three-dimensional structure model of the conjugate;
A comprehensive suitability evaluation unit that generates a comprehensive suitability index of the three-dimensional structure model of the conjugate based on the environmental suitability index of the three-dimensional structure model of the conjugate and the distance-dependent potential energy index;
An output unit for outputting the comprehensive suitability index;
A combined body model evaluation apparatus comprising: The combined body model evaluation apparatus according to claim 1,
The environmental suitability evaluation unit further generates water compatibility of the entire three-dimensional structure model of the conjugate and an environmental suitability index for the protein internal environment based on the secondary structure formed by the amino acid residue. A combined model evaluation device. In the combined body model evaluation apparatus of Claim 1 or 2,
A structural complementarity evaluation unit that generates a structural complementarity index of the conjugate based on the structural complementarity between the polypeptides in the three-dimensional structure model of the conjugate;
The comprehensive compatibility evaluation unit further generates the comprehensive compatibility index based on the structural complementarity index. In the combined body model evaluation apparatus according to claim 3,
The structural complementarity evaluation unit is:
Shape complementarity between each of the polypeptides,
Desolvation of each of the polypeptides;
Electrostatic interaction between each of the polypeptides;
Based on the above, a conjugate model evaluation apparatus, which generates a structural complementarity index of the conjugate. A conjugate model evaluation apparatus for evaluating a conjugate model of a plurality of polypeptides,
A conjugate model acquisition unit that acquires a plurality of three-dimensional structure models of the conjugates generated based on the three-dimensional structure model of each of the plurality of polypeptides;
A structural complementarity evaluation unit that generates a structural complementarity index of the conjugate based on the structural complementarity between the polypeptides in the three-dimensional structure model of the conjugate;
A conjugate model selection unit that selects a three-dimensional structure model of the conjugate whose structural complementarity index is equal to or greater than a threshold value from the three-dimensional structure models of the plurality of conjugates;
Based on the peripheral polarity for each amino acid residue in the three-dimensional structure model of the selected conjugate and the degree of solvent exposure of the side chain for each amino acid residue, the water solubility of the whole three-dimensional model of the conjugate and the protein interior An environmental suitability evaluation unit that generates an environmental suitability index for the environment;
A distance-dependent type that generates a distance-dependent potential energy index of the entire three-dimensional structure model of the selected conjugate based on a distance-dependent potential energy for each amino acid residue pair in the three-dimensional structure model of the selected conjugate A potential energy evaluation unit;
Based on the environmental suitability index of the three-dimensional structure model of the selected conjugate and the distance-dependent potential energy index, an overall suitability for generating a total suitability index of the three-dimensional structure model of the selected conjugate An evaluation unit;
An output unit for outputting the comprehensive suitability index;
A combined body model evaluation apparatus comprising: In the combined body model evaluation apparatus of Claim 5,
The environmental suitability evaluation unit further generates water compatibility of the entire three-dimensional structure model of the conjugate and an environmental suitability index for the protein internal environment based on the secondary structure formed by the amino acid residue. A combined model evaluation device. The combined body model evaluation apparatus according to claim 5 or 6,
The comprehensive compatibility evaluation unit further generates the comprehensive compatibility index based on the structural complementarity index. In the combined body model evaluation apparatus in any one of Claims 5 thru | or 7,
The structural complementarity evaluation unit is:
Shape complementarity between each of the polypeptides,
Desolvation of each of the polypeptides;
Electrostatic interaction between each of the polypeptides;
Based on the above, a conjugate model evaluation apparatus, which generates a structural complementarity index of the conjugate. In the combined body model evaluation apparatus in any one of Claims 1 thru | or 8,
Of the amino acid residues of each polypeptide, a binding participation information acquisition unit for acquiring known binding participation information that defines amino acid residues involved in binding to other polypeptides,
A binding participation index generation unit that generates a binding participation index in the entire three-dimensional structure model of the conjugate based on the known binding participation information of the three-dimensional structure model of each polypeptide;
Further comprising
The comprehensive suitability evaluation unit further generates the comprehensive suitability index based on the binding participation index. In the combined body model evaluation apparatus in any one of Claims 1 thru | or 9,
Each model acquisition unit for acquiring a three-dimensional structure model of each of the plurality of polypeptides;
A conjugate model generation unit for generating a three-dimensional structure model of the conjugate based on the three-dimensional structure model of each of the plurality of polypeptides;
The combined body model evaluation apparatus further comprising: The combined body model evaluation apparatus according to claim 10,
Each sequence obtaining unit for obtaining information defining an amino acid sequence of each of the plurality of polypeptides;
A single model generation unit that generates a three-dimensional structure model of each of the plurality of polypeptides based on information defining the amino acid sequences of each of the plurality of polypeptides;
The combined body model evaluation apparatus further comprising: The combined body model evaluation apparatus according to claim 1,
The total suitability evaluation unit normalizes each index of the three-dimensional structure model of the combined body, and generates a total compatibility index of the three-dimensional structure model of the combined body based on each normalized index. An apparatus for evaluating a combined body model. A conjugate model evaluation method for evaluating a conjugate model of a plurality of polypeptides,
Obtaining a three-dimensional structure model of the conjugate generated based on the three-dimensional structure model of each of the plurality of polypeptides;
Based on the peripheral polarity for each amino acid residue in the three-dimensional structure model of the conjugate and the degree of solvent exposure of the side chain for each amino acid residue, the water solubility of the whole three-dimensional model of the conjugate and the environment for the internal environment of the protein Generating a fitness index; and
Generating a distance-dependent potential energy index for the entire three-dimensional structure model of the conjugate based on a distance-dependent potential energy for each amino acid residue pair in the three-dimensional structure model of the conjugate;
Generating an overall suitability index of the 3D structure model of the conjugate based on the environmental suitability index of the 3D structure model of the conjugate and the distance-dependent potential energy index;
Outputting the comprehensive suitability index;
A combined model evaluation method comprising: A conjugate model evaluation method for evaluating a conjugate model of a plurality of polypeptides,
Obtaining a three-dimensional structure model of the plurality of conjugates generated based on the three-dimensional structure model of each of the plurality of polypeptides;
Generating a structural complementarity index for the conjugate based on the structural complementarity between the polypeptides in the conformational model of the conjugate;
Selecting the three-dimensional structure model of the conjugate whose structural complementarity index is equal to or greater than a threshold from the three-dimensional structure models of the plurality of conjugates;
Based on the peripheral polarity for each amino acid residue in the three-dimensional structure model of the selected conjugate and the degree of solvent exposure of the side chain for each amino acid residue, the water solubility of the whole three-dimensional model of the conjugate and the protein interior Generating an environmental suitability index for the environment;
Generating a distance-dependent potential energy index for the entire three-dimensional structure model of the selected conjugate based on the distance-dependent potential energy of each amino acid residue pair in the three-dimensional structure model of the selected conjugate;
Generating an overall suitability index of the 3D structure model of the selected conjugate based on the environmental suitability index of the 3D structure model of the selected conjugate and the distance-dependent potential energy;
A combined model evaluation method comprising: A conjugate model evaluation program for causing a computer to execute a process for evaluating a conjugate model of a plurality of polypeptides,
Obtaining a three-dimensional structure model of the conjugate generated based on the three-dimensional structure model of each of the plurality of polypeptides;
Based on the peripheral polarity for each amino acid residue in the three-dimensional structure model of the conjugate and the degree of solvent exposure of the side chain for each amino acid residue, the water solubility of the whole three-dimensional model of the conjugate and the environment for the internal environment of the protein Generating a fitness index; and
Generating a distance-dependent potential energy index for the entire three-dimensional structure model of the conjugate based on a distance-dependent potential energy for each amino acid residue pair in the three-dimensional structure model of the conjugate;
Generating an overall suitability index of the 3D structure model of the conjugate based on the environmental suitability index of the 3D structure model of the conjugate and the distance-dependent potential energy index;
Outputting the comprehensive suitability index;
A computer-implemented model evaluation program characterized by causing a computer to execute. A conjugate model evaluation program for causing a computer to execute a process for evaluating a conjugate model of a plurality of polypeptides,
Obtaining a three-dimensional structure model of the plurality of conjugates generated based on the three-dimensional structure model of each of the plurality of polypeptides;
Generating a structural complementarity index for the conjugate based on the structural complementarity between the polypeptides in the conformational model of the conjugate;
Selecting the three-dimensional structure model of the conjugate whose structural complementarity index is equal to or greater than a threshold from the three-dimensional structure models of the plurality of conjugates;
Based on the peripheral polarity for each amino acid residue in the three-dimensional structure model of the selected conjugate and the degree of solvent exposure of the side chain for each amino acid residue, the water solubility of the whole three-dimensional model of the conjugate and the protein interior Generating an environmental suitability index for the environment;
Generating a distance-dependent potential energy index for the entire three-dimensional structure model of the selected conjugate based on the distance-dependent potential energy of each amino acid residue pair in the three-dimensional structure model of the selected conjugate;
Generating an overall suitability index of the 3D structure model of the selected conjugate based on the environmental suitability index of the 3D structure model of the selected conjugate and the distance-dependent potential energy;
A computer-implemented model evaluation program characterized by causing a computer to execute.

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