Intermolecular interaction analysis device, intermolecular interaction analysis method, and program

Abstract

An intermolecular interaction analysis device (1) is provided with: a contact surface definition unit (30) that defines, as a contact surface, a surface in which the partial electron density of a molecule A calculated by an electron density calculation unit (10) and the partial electron density of a molecule B calculated by an electron density calculation unit (20) are equal; an electrostatic potential calculation unit (40) that removes the contribution of the charged amino acid residue corresponding to the charge of the molecule (A) and calculates the partial electrostatic potential of the molecule (A) at the contact surface by the FMO method; and an electrostatic potential calculation unit (50) that removes the contribution of the charged amino acid residue corresponding to the charge of the molecule (B) and calculates the partial electrostatic potential of the molecule (B) at the contact surface by the FMO method.

Description

Technical Field

[0001] The present invention relates to an intermolecular interaction analysis device, an intermolecular interaction analysis method, and a program. Background Art

[0002] Based on the three-dimensional structural data of the ligand binding site of the protein that is the target of drug development and the three-dimensional structural data of the compound, the molecular interaction between the ligand binding site and the compound can be evaluated. By evaluating the molecular interaction based on computational chemistry, it is possible to design compounds that bind to the ligand binding site with higher affinity. In addition, virtual screening that comprehensively evaluates many compounds can be performed.

[0003] For example, Patent Document 1 discloses a protein interaction analysis device that generates data related to the interaction using surface shape data of a ligand binding site, electrostatic potential distribution data of the ligand binding site, and three-dimensional structural data on a ligand interacting with the ligand binding site.

[0004] Many biological functions such as signal transduction, transport, and metabolism in the body are controlled by protein-protein interactions (PPI), which is a general term for interactions between protein molecules. Antibodies that bind to target proteins through PPIs have high affinity and specificity, so they are used as drugs. Antibodies can target proteins that small molecule compounds cannot target, so the development of antibody drugs has increased in recent years.

[0005] For example, if programmed death-ligand 1 (PD-L1) of cancer cells binds to programmed death-1 (PD-1) of T cells, the cytokines produced by T cells decrease, and the signal that inhibits the activity of T cells is transmitted. The contact surface between PD-1 and PD-L1 is close to a plane and does not have a pocket-like three-dimensional structure, so it is difficult to block it with small molecule compounds. On the other hand, nivolumab, an antibody drug, binds to PD-1 through PPI and can block the binding of PD-1 and PD-L1. In this way, a detailed understanding of PPI is important in clarifying the functions of organisms and developing antibody drugs.

[0006] In addition, in non-patent document 1, in a protein complex, the partial electron density of each protein is calculated by the fragment molecular orbital method, and the surface with the same partial electron density is defined as the contact surface. In addition, non-patent document 1 discloses the following technology: by adding ions to eliminate the charge of each protein, the partial electrostatic potential of the contact surface is neutralized. In this way, the charge distribution of the two molecules at the binding surface can be estimated and the electrostatic interaction can be visualized.

[0007] Patent Document 1: International Publication No. 2019 / 235567

[0008] Non-patent literature 1: H.Ozono and T.Ishikawa, "Visualization of the InterfacialElectrostatic Complementarity: A Method for Analysis of Protein-ProteinInteraction Based on Ab Initio Quantum Chemical Calculations", JChem.TheoryComput., 2021, 17, 5600-5610

[0009] As disclosed in Patent Document 1, the computational chemistry analysis of intermolecular interactions is mainly applied to the analysis of interactions between proteins and small molecule compounds. In the analysis of PPI, a large contact surface must be considered, and complex interactions formed by multiple amino acid residues need to be analyzed. In the existing computational chemistry analysis of intermolecular interactions, it is difficult to analyze PPI with high precision.

[0010] In addition, in Non-Patent Document 1, since the calculation result depends on the type or position of the additional ions, further improvements are required in that the accuracy is reduced and the amount of calculation increases because the calculation of the additional ions must be further performed. Summary of the invention

[0011] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an intermolecular interaction analysis device, an intermolecular interaction analysis method, and a program capable of evaluating intermolecular interactions involving a plurality of amino acid residues with high accuracy.

[0012] A molecular interaction analysis device according to a first aspect of the present invention comprises:

[0013] A first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds;

[0014] a second electron density calculation unit, for calculating partial electron density of the second molecule by a fragment molecular orbital method based on three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position interacting with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds;

[0015] a contact surface defining unit, defining a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface;

[0016] a first electrostatic potential calculation unit that, when the first molecule has a charge, removes a contribution of a charged amino acid residue corresponding to the charge of the first molecule and calculates a partial electrostatic potential of the first molecule at the contact surface by a fragment molecular orbital method; and

[0017] The second electrostatic potential calculation unit calculates the partial electrostatic potential of the second molecule at the contact surface by a fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the second molecule, when the second molecule has a charge.

[0018] The contact surface defining unit may define a surface where the partial electron density of the first molecule is greater than or equal to a reference value as the contact surface.

[0019] Alternatively, the first electrostatic potential calculation unit may be:

[0020] In the case where the first molecule has a positive charge of +n, n arginine residues and lysine residues contained in the first molecule are selected as the charged amino acid residues in descending order of distance from the contact surface, and the partial electrostatic potential of the entire first molecule is calculated by removing the selected charged amino acid residues.

[0021] In the case where the first molecule has a negative charge of -n, n aspartic acid and glutamic acid residues contained in the first molecule are selected in descending order of distance from the contact surface as the charged amino acid residues, and the partial electrostatic potential of the entire first molecule is calculated by removing the selected charged amino acid residues.

[0022] The second electrostatic potential calculation unit is:

[0023] In the case where the second molecule has a positive charge of +n, n arginine residues and lysine residues contained in the second molecule are selected as the charged amino acid residues in descending order of distance from the contact surface, and the partial electrostatic potential of the second molecule as a whole is calculated by removing the selected charged amino acid residues.

[0024] When the second molecule has a negative charge of -n, n aspartic acid and glutamic acid residues contained in the second molecule are selected as the charged amino acid residues in descending order of distance from the contact surface, and the partial electrostatic potential of the selected charged amino acid residues is removed to calculate the partial electrostatic potential of the second molecule as a whole.

[0025] A molecular interaction analysis device according to a second aspect of the present invention includes:

[0026] A first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds;

[0027] a second electron density calculation unit, for calculating partial electron density of the second molecule by a fragment molecular orbital method based on three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position interacting with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds;

[0028] a contact surface defining unit that defines a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface; and

[0029] The dispersion force evaluation unit evaluates the dispersion force based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

[0030] The contact surface defining unit may define a surface where the partial electron density of the first molecule is greater than or equal to a reference value as the contact surface.

[0031] The dispersion force evaluation unit may evaluate the dispersion force using an index indicating an overlap of partial electron density calculated from a sum of a partial electron density of the first molecule and a partial electron density of the second molecule at the contact surface.

[0032] A molecular interaction analysis device according to a third aspect of the present invention includes:

[0033] A first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds;

[0034] a second electron density calculation unit, for calculating partial electron density of the second molecule by a fragment molecular orbital method based on three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position interacting with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds;

[0035] a contact surface defining unit, defining a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface;

[0036] a first electrostatic potential calculation unit, which, when the first molecule has a charge, removes a contribution of a charged amino acid residue corresponding to the charge of the first molecule and calculates a partial electrostatic potential of the first molecule at the contact surface by a fragment molecular orbital method;

[0037] a second electrostatic potential calculation unit that, when the second molecule has a charge, removes a contribution of a charged amino acid residue corresponding to the charge of the second molecule and calculates a partial electrostatic potential of the second molecule at the contact surface by a fragment molecular orbital method; and

[0038] The dispersion force evaluation unit evaluates the dispersion force based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

[0039] A fourth aspect of the present invention relates to a method for analyzing molecular interactions, comprising:

[0040] Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds;

[0041] calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds;

[0042] A surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule is defined as a contact surface;

[0043] When the first molecule has a charge, the partial electrostatic potential of the first molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the first molecule;

[0044] When the second molecule has a charge, the partial electrostatic potential of the second molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residue corresponding to the charge of the second molecule.

[0045] A fifth aspect of the present invention relates to a method for analyzing molecular interactions, comprising:

[0046] Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds;

[0047] calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds;

[0048] defining a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface; and

[0049] The dispersion force is evaluated based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

[0050] A molecular interaction analysis method according to a sixth aspect of the present invention comprises:

[0051] Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds;

[0052] calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds;

[0053] A surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule is defined as a contact surface;

[0054] When the first molecule has a charge, the partial electrostatic potential of the first molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the first molecule;

[0055] When the second molecule has a charge, the partial electrostatic potential of the second molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the second molecule; and

[0056] The dispersion force is evaluated based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

[0057] A program according to a seventh aspect of the present invention causes a computer to function as a first electron density calculation unit, a second electron density calculation unit, a contact surface definition unit, a first electrostatic potential calculation unit, and a second electrostatic potential calculation unit.

[0058] The first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds.

[0059] The second electron density calculation unit calculates partial electron density of the second molecule by a fragment molecular orbital method for three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and includes a plurality of amino acid residues bonded via peptide bonds,

[0060] The contact surface defining unit defines a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface,

[0061] The first electrostatic potential calculation unit calculates the partial electrostatic potential of the first molecule at the contact surface by a fragment molecular orbital method, removing the contribution of the charged amino acid residues corresponding to the charge of the first molecule when the first molecule has a charge.

[0062] When the second molecule has a charge, the second electrostatic potential calculation unit calculates the partial electrostatic potential of the second molecule at the contact surface by a fragment molecular orbital method, excluding a contribution of a charged amino acid residue corresponding to the charge of the second molecule.

[0063] The program according to the eighth aspect of the present invention causes a computer to function as a first electron density calculation unit, a second electron density calculation unit, a contact surface definition unit, and a dispersion force evaluation unit,

[0064] The first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds.

[0065] The second electron density calculation unit calculates partial electron density of the second molecule by a fragment molecular orbital method for three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and includes a plurality of amino acid residues bonded via peptide bonds,

[0066] The contact surface defining unit defines a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface,

[0067] The dispersion force evaluation unit evaluates the dispersion force based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

[0068] A program according to a ninth aspect of the present invention causes a computer to function as a first electron density calculation unit, a second electron density calculation unit, a contact surface definition unit, a first electrostatic potential calculation unit, a second electrostatic potential calculation unit, and a dispersion force evaluation unit.

[0069] The first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds.

[0070] The second electron density calculation unit calculates partial electron density of the second molecule by a fragment molecular orbital method for three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and includes a plurality of amino acid residues bonded via peptide bonds,

[0071] The contact surface defining unit defines a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface,

[0072] The first electrostatic potential calculation unit calculates the partial electrostatic potential of the first molecule at the contact surface by a fragment molecular orbital method, removing the contribution of the charged amino acid residues corresponding to the charge of the first molecule when the first molecule has a charge.

[0073] The second electrostatic potential calculation unit calculates the partial electrostatic potential of the second molecule at the contact surface by a fragment molecular orbital method, removing the contribution of the charged amino acid residues corresponding to the charge of the second molecule when the second molecule has a charge.

[0074] The dispersion force evaluation unit evaluates the dispersion force based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

[0075] The intermolecular interaction analysis device according to the tenth aspect of the present invention comprises:

[0076] Memory, which stores programs; and

[0077] The CPU (central processing unit) reads the above program from the above memory and executes it.

[0078] The above CPU performs the following processing:

[0079] Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds;

[0080] calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds;

[0081] A surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule is defined as a contact surface;

[0082] When the first molecule has a charge, excluding the contribution of the charged amino acid residues corresponding to the charge of the first molecule, the partial electrostatic potential of the first molecule at the contact surface is calculated by the fragment molecular orbital method; and

[0083] When the second molecule has a charge, the partial electrostatic potential of the second molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residue corresponding to the charge of the second molecule.

[0084] The intermolecular interaction analysis device according to the eleventh aspect of the present invention comprises:

[0085] Memory, which stores programs; and

[0086] The CPU (central processing unit) reads the above program from the above memory and executes it.

[0087] The above CPU performs the following processing:

[0088] Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds;

[0089] calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds;

[0090] defining a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface; and

[0091] The dispersion force is evaluated based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

[0092] The molecular interaction analysis device according to the twelfth aspect of the present invention comprises:

[0093] Memory, which stores programs; and

[0094] The CPU (central processing unit) reads the above program from the above memory and executes it.

[0095] The above CPU performs the following processing:

[0096] Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds;

[0097] calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds;

[0098] A surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule is defined as a contact surface;

[0099] When the first molecule has a charge, the partial electrostatic potential of the first molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the first molecule;

[0100] When the second molecule has a charge, the partial electrostatic potential of the second molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the second molecule; and

[0101] The dispersion force is evaluated based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

[0102] Effects of the Invention

[0103] According to the present invention, it is possible to evaluate the interaction between molecules involving a plurality of amino acid residues with high accuracy. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] Figure 1 It is a diagram showing the configuration of the intermolecular interaction analysis device according to the first embodiment of the present invention.

[0105] Figure 2 This figure shows the calculation range of partial electron density and the concept of three-dimensional grid data.

[0106] Figure 3A This is a diagram showing the partial electrostatic potential of nivolumab as an example of a contact surface to which information on the partial electrostatic potential is added.

[0107] Figure 3BThis is a diagram showing the partial electrostatic potential of PD-1 as an example of a contact surface to which information related to the partial electrostatic potential is added.

[0108] Figure 4 Yes means Figure 1 Block diagram of the hardware composition of the intermolecular interaction analysis device.

[0109] Figure 5 Yes means Figure 1 FIG. 1 is a flowchart of the electrostatic potential evaluation process of the intermolecular interaction analysis apparatus.

[0110] Figure 6 It is a diagram showing the configuration of an intermolecular interaction analysis device according to Embodiment 2 of the present invention.

[0111] Figure 7 This is a diagram showing an example of a contact surface to which an index indicating the overlap of partial electron densities is added.

[0112] Figure 8 Yes means Figure 6 Block diagram of the hardware composition of the intermolecular interaction analysis device.

[0113] Fig. 9 Yes means Figure 6 FIG. 1 is a flowchart of the dispersion force evaluation process of the intermolecular interaction analysis apparatus. DETAILED DESCRIPTION

[0114] Hereinafter, the embodiments of the present invention will be described with reference to the accompanying drawings. In each of the accompanying drawings, the same or equivalent parts are marked with the same reference numerals. In addition, the present invention is not limited by the following embodiments and the accompanying drawings. In addition, in the following embodiments, expressions such as "having", "including" or "containing" also include the meaning of "consisting of" or "consisting of".

[0115] Implementation Method 1

[0116] Embodiment 1 of the present invention is described. The intermolecular interaction analysis device of the information processing device involved in this embodiment analyzes the intermolecular interaction between molecule A (first molecule) and molecule B (second molecule). Molecule A and molecule B each contain a plurality of amino acid residues bound by peptide bonds. As molecules A and B, for example, proteins, peptides, and antibodies are listed. Molecule A and molecule B may also be molecules containing a plurality of amino acid chains bound by bonds other than peptide bonds, such as disulfide bonds, like antibodies. Intermolecular interaction refers to electrostatic interaction, van der Waals force, dipole interaction, dispersion force, hydrogen bond, hydrophobic interaction, etc., acting between molecules A and B.

[0117] The intermolecular interaction analysis device according to the present embodiment is implemented on a computer. That is, the intermolecular interaction analysis device is an information processing device that specifically implements information processing based on software using hardware resources.

[0118] like Figure 1 As shown, the intermolecular interaction analysis device 1 inputs the three-dimensional structure data 2 of molecule A and the three-dimensional structure data 3 of molecule B. The three-dimensional structure data 2 is information indicating the position of each atom constituting molecule A in three-dimensional space, specifically, the coordinate data of each atom constituting molecule A determined by X-ray crystal structure analysis or NMR. The three-dimensional structure data 2 can be obtained from the Protei Data Bank (PDB: Protein Data Bank) and the like. When the coordinate data obtained from the PDB is used as the three-dimensional structure data 2, water molecules can also be deleted from the coordinate data, hydrogen atoms can be added to the three-dimensional structure, and the N-terminus and the C-terminus can be terminated with -COCH3 and -NHCH3, etc., respectively. In addition, the coordinate data of the three-dimensional structure optimized using a known force field can also be used as the three-dimensional structure data 2. The three-dimensional structure data 3 is the same as the three-dimensional structure data 2.

[0119] The intermolecular interaction analysis device 1 performs calculations on the three-dimensional structure data 2 and the three-dimensional structure data 3, and outputs evaluation information 4 on the intermolecular interaction between the molecule A and the molecule B. The evaluation information 4 includes not only the magnitude of the electrostatic potential contributing to the interaction between the molecule A and the molecule B, but also the correspondence between the electrostatic potential of the molecule A and the electrostatic potential of the molecule B, and the like.

[0120] The structure of the molecular interaction analysis device 1 is described in detail. Figure 1 As shown, the intermolecular interaction analysis device 1 includes an electron density calculation unit 10 , an electron density calculation unit 20 , a contact surface definition unit 30 , an electrostatic potential calculation unit 40 , and an electrostatic potential calculation unit 50 .

[0121] The electron density calculation unit 10 calculates the partial electron density of molecule A by the fragment molecular orbital (FMO) method for the three-dimensional structure data 2 of molecule A. The FMO method is a method of dividing a giant molecular system such as a protein and a polymer into smaller fragments of several tens of atomic units, and performing multiple calculations based on the non-empirical molecular orbital method for a single fragment (monomer) and a fragment pair (dimer) to calculate the total energy of the molecule and the inter-fragment interaction energy (IFIE), etc. The FMO method can use a known software program such as PAICS.

[0122] Here, the calculation of electron density based on the FMO method is explained. First, the protein is divided into fragments for each amino acid residue, and the protein is divided into smaller fragments. The calculation of monomers and dimers requires the calculation based on the electron density of the surrounding fragments taking into account the electrostatic potential, so a monomer SCC (monomer selfconsistent charge) calculation is performed to determine the electron density of each fragment. In the monomer SCC calculation, the initial electron density is determined, and the monomer calculation of each fragment is performed in the presence of an electrostatic potential based on the initial electron density. If the calculation for all fragments is completed, a new electron density different from the initial electron density described above is obtained. Next, the new electron density is used as the initial electron density and the calculation is performed in the same way. This process is repeated until it becomes a self-consistent electron density, which becomes the final electron density. Then, considering the electrostatic potential generated by the final electron density, monomer calculations and dimer calculations are performed. Finally, the overall properties are calculated based only on the calculation results of the monomer and dimer. As shown in Formula 1, the energy of the monomer (E I ) and the energy of the dimer (E IJ ) to find the total energy.

[0123] [Number 1]

[0124]

[0125] Formula 1 can be replaced by the following Formula 2.

[0126] [Number 2]

[0127]

[0128] The first term on the right side of equation 2 is the energy of the monomer minus the electrostatic potential from other fragments. The second term on the right side represents the interaction energy between fragments, i.e., IFIE.

[0129] The electron density was calculated by the FMO method, as shown in Equation 3, based on the electron density of the monomer at position r (ρ I (r)) and the electron density of the dimer (ρ IJ (r)) is found.

[0130] [Number 3]

[0131]

[0132] return Figure 1 The electron density calculation unit 20 calculates the partial electron density of molecule B by the FMO method for the three-dimensional structure data 3 of molecule B arranged at a position interacting with molecule A relative to the position of molecule A.

[0133] The contact surface definition unit 30 defines the contact surface based on the partial electron density of molecule A and the partial electron density of molecule B. In the complex of molecule A and molecule B, the electron density of the entire complex (ρ total (r)) can be divided into the partial electron density of molecule A (ρ part－A (r)) and the partial electron density of molecule B (ρ part－B (r)), the partial electron density of molecule A and the partial electron density of molecule B are calculated by equation 4 and equation 5 respectively.

[0134] [Number 4]

[0135]

[0136] In Formula 4, which is the partial electron density of molecule A, the first term on the right is the contribution of the monomer in molecule A, and the second term is the contribution of the dimer in molecule A. The third term represents the contribution of the dimer between molecule A and molecule B. The same is true for Formula 5, which is the partial electron density of molecule B. Formula 6 shows that if the partial electron density of molecule A and the partial electron density of molecule B are added, the electron density of the entire complex is obtained.

[0137] For example, part of the electron density is calculated using 3D grid data. First, Figure 2 In the molecules A and B shown in the figure, the range D of the grid is set. The range D is set in an arbitrary way to include amino acid residues that contribute to the interaction between molecules A and B. For example, the range D is a range that includes amino acid residues of molecule A within a distance L from molecule B and amino acid residues of molecule B within a distance L from molecule A. The distance L is appropriately set in consideration of the sizes of molecules A and B, the size of the interaction range, etc. Next, the range D is demarcated with a grid that is a cube. The length of one side of the grid is appropriately set, for example, like Figure 2 As shown in FIG. 1 , if a grid cell composed of eight points r1 to r8 is considered, the electron density calculation unit 10 calculates the partial electron density of r1 to r8 for molecule A. The partial electron density of the grid cell calculated for molecule A (the partial electron density of molecule A) is taken as the center point r of the grid cell. c On the other hand, the partial electron density of the grid cell calculated for molecule B by the electron density calculation unit 20 (partial electron density of molecule B) is similarly obtained.

[0138] The contact surface definition unit 30 defines the surface where the partial electron density of molecule A is equal to the partial electron density of molecule B as the contact surface S. In the above example, when the partial electron density of molecule A is equal to the partial electron density of molecule B, point r cThe contact surface S is a point that forms the contact surface S. Here, the size of the contact surface S depends on the size of the range D, so it is preferred that the contact surface definition unit 30 sets the partial electron density of the molecule A to the reference value ρ c The above surface is defined as the contact surface S. c For example, 10 －4 atomic units (au) and above.

[0139] return Figure 1 The electrostatic potential calculation unit 40 calculates the partial electrostatic potential of molecule A at the contact surface S by the FMO method. Here, the calculation of the electrostatic potential based on the FMO method is described. The electrostatic potential (φ) of the entire complex composed of molecules A and B is total (r)) According to the electrostatic potential of the monomer at position r (φ I (r)), the electrostatic potential of the dimer (φ IJ (r)), the position of the atom R α , and the nuclear charge Z α It is calculated as shown in Formula 7.

[0140] [Number 5]

[0141]

[0142] φ total (r) can be divided into the partial electrostatic potential of molecule A (φ part－A (r)) and the partial electrostatic potential of molecule B (φ part－B (r)), the partial electrostatic potential of molecule A and the partial electrostatic potential of molecule B are calculated according to equation 8 and equation 9, respectively.

[0143] [Number 6]

[0144]

[0145] φ total (r) = φ paart-A (r)+φ part-B (r) (Equation 10)

[0146] In equation 8, which is the partial electrostatic potential of molecule A, the first term on the right is the contribution of the monomer in molecule A, and the second term is the contribution of the dimer in molecule A. The third term is the contribution due to the nuclei in molecule A. The fourth term represents the contribution of the dimer between molecule A and molecule B. The same is true for equation 9, which is the partial electrostatic potential of molecule B. Equation 10 shows that if the partial electrostatic potential of molecule A and the partial electrostatic potential of molecule B are added, the electrostatic potential of the entire complex is obtained.

[0147] When molecule A has a charge, the partial electrostatic potential at the contact surface S is biased. Even when the protein has a charge, the protein is neutralized by the counterions present in the solution in the organism. In order to retain the original partial electrostatic potential state at the contact surface S and suppress the influence of the overall charge, when molecule A has a charge, the electrostatic potential calculation unit 40 removes the contribution of the charged amino acid residues equivalent to the charge of molecule A and calculates the partial electrostatic potential of molecule A at the contact surface S by the FMO method. More specifically, when molecule A has a positive charge of +n, the electrostatic potential calculation unit 40 selects n of the arginine residues and lysine residues contained in molecule A as charged amino acid residues in the order of the distance from the contact surface S from the longest to the shortest. Then, the electrostatic potential calculation unit 40 removes the partial electrostatic potential of the selected charged amino acid residues and calculates the partial electrostatic potential of the entire molecule A. On the other hand, when molecule A has a negative charge of -n, the electrostatic potential calculation unit 40 selects n of the aspartic acid and glutamic acid contained in molecule A as charged amino acid residues in the order of the distance from the contact surface S from the longest to the shortest. The electrostatic potential calculation unit 40 removes the partial electrostatic potential of the selected charged amino acid residues and calculates the partial electrostatic potential of the entire molecule A. When the charge of molecule A is 0, the electrostatic potential calculation unit 40 calculates the partial electrostatic potential of molecule A at the contact surface S without removing the partial electrostatic potential of the charged amino acid residues.

[0148] For example, when molecule A has a charge of -3, the electrostatic potential calculation unit 40 calculates the distances between all aspartic acid and glutamic acid contained in molecule A and the contact surface S, sorts them in order of distance from long to short, removes the partial electrostatic potentials of the first three charged amino acid residues, and calculates the partial electrostatic potential of molecule A. On the contrary, when molecule A has a charge of +2, the electrostatic potential calculation unit 40 calculates the distances between all arginine or lysine contained in molecule A and the contact surface S, sorts them in order of distance from long to short, removes the partial electrostatic potentials of the first two charged amino acid residues, and calculates the partial electrostatic potential of molecule A.

[0149] In addition, the distance from the closest atom of molecule B to the charged amino acid residue of molecule A can also be calculated as the distance between the contact surface S and the charged amino acid residue. In addition, when calculating the distance from the contact surface S or the atom to the charged amino acid residue, as the position of the charged amino acid residue, either the position of the α carbon or the average value of the coordinates of all atoms constituting the charged amino acid residue can be used.

[0150] The electrostatic potential calculation unit 50 calculates the partial electrostatic potential of the molecule B at the contact surface S by the FMO method, similarly to the electrostatic potential calculation unit 40. When the molecule B has a charge, the electrostatic potential calculation unit 50 calculates the partial electrostatic potential of the molecule B at the contact surface S by the FMO method, similarly to the electrostatic potential calculation unit 40, by removing the contribution of the charged amino acid residues corresponding to the charge of the molecule B.

[0151] The partial electrostatic potential of molecule A and the partial electrostatic potential of molecule B obtained as evaluation information 4 by the electrostatic potential calculation unit 40 and the electrostatic potential calculation unit 50 can be displayed on the contact surface S by color classification corresponding to the respective values. For example, Figure 3A The partial electrostatic potential of nivolumab at the contact surface S of the complex between PD-1 and the antibody nivolumab that binds to PD-1 is shown. Figure 3B represents the partial electrostatic potential of PD-1 at the contact surface S of the complex between PD-1 and the antibody nivolumab that binds to PD-1. Figure 3A and Figure 3B , then at the contact surface S, the positive and negative electric charges are almost corresponding, indicating the high electric affinity between PD-1 and nivolumab. For example, the electrostatic potential calculation unit 40 calculates the total φ of the attractive force interaction (opposite signs) of the grid of the contact surface S － The sum of the repulsive interactions (same sign) with the mesh grid of the contact surface S is φ + , calculate φ － Relative to φ － With φ + The ratio of the sum W － As evaluation information 4. － It can be used as an index of the correspondence between the electrostatic potential of molecule A and the electrostatic potential of molecule B (electrostatic complementarity).

[0152] Figure 1 The molecular interaction analysis device 1 shown in the figure is, for example, composed of Figure 4 Specifically, the molecular interaction analysis device 1 is composed of a CPU (Central Processing Unit) 21 responsible for controlling the entire device, a main storage unit 22 as a work area of ​​the CPU 21, an external storage unit 23 storing the operation program of the CPU 21, an operation unit 24, a display unit 25, a communication interface 26, and an internal bus 27 connecting these components.

[0153] The main storage unit 22 is composed of a RAM (Random Access Memory) etc. The three-dimensional structure data 2, the three-dimensional structure data 3, the electrostatic potential evaluation program 28, the FMO method calculation program 29, the data 31 representing the charge of the molecule A corresponding to the three-dimensional structure data 2, and the data 32 representing the charge of the molecule B corresponding to the three-dimensional structure data 3 are loaded from the external storage unit 23 to the main storage unit 22. In addition, the main storage unit 22 is also used as a working area (temporary storage area for data) of the CPU 21.

[0154] The external storage unit 23 is composed of a nonvolatile memory such as a flash memory and a hard disk. The external storage unit 23 stores in advance an electrostatic potential evaluation program 28 and an FMO method calculation program 29 for the CPU 21 to execute. In addition, in addition to the three-dimensional structure data 2 and the three-dimensional structure data 3, the external storage unit 23 also stores data 31 representing the charge of the molecule A and data 32 representing the charge of the molecule B.

[0155] The operation unit 24 is composed of devices such as a keyboard and a mouse, and an interface device that connects these devices to the internal bus 27 .

[0156] The display unit 25 is composed of display devices such as a CRT (Cathode Ray Tube) and a liquid crystal monitor.

[0157] The communication interface 26 is an interface for transmitting and receiving data with an external device. The three-dimensional structure data 2, the three-dimensional structure data 3, the data 31 indicating the charge of the molecule A, the data 32 indicating the charge of the molecule B, etc. are transmitted and received via the communication interface 26.

[0158] Next, the intermolecular interaction analysis method realized by the operation of the intermolecular interaction analysis apparatus 1 according to the present embodiment, that is, the electrostatic potential evaluation process executed by the intermolecular interaction analysis apparatus 1 will be described.

[0159] First, the electrostatic potential evaluation program 28 and the FMO method calculation program 29 are read from the external storage unit 23 into the main storage unit 22 , and the CPU 21 executes the electrostatic potential evaluation program 28 to perform the electrostatic potential evaluation process.

[0160] like Figure 5 As shown, the molecular interaction analysis device 1 reads the three-dimensional structure data 2, the three-dimensional structure data 3, the data 31 representing the charge of the molecule A, and the data 32 representing the charge of the molecule B (step S1). Here, the three-dimensional structure data 2, the three-dimensional structure data 3, the data 31 representing the charge of the molecule A, and the data 32 representing the charge of the molecule B are read from the external storage unit 23 into the main storage unit 22.

[0161] The electron density calculation unit 10 reads the FMO method calculation program 29 from the external storage unit 23 into the main storage unit 22, and calculates the partial electron density of molecule A using the three-dimensional structure data 2 (step S2). The data representing the partial electron density of molecule A is stored in the main storage unit 22 and the external storage unit 23. Next, the electron density calculation unit 20 calculates the partial electron density of molecule B using the three-dimensional structure data 3 (step S3). The data representing the partial electron density of molecule B is stored in the main storage unit 22 and the external storage unit 23.

[0162] Next, the contact surface definition unit 30 refers to the data representing the partial electron density of molecule A and the data representing the partial electron density of molecule B stored in the main storage unit 22 to define the contact surface S (step S4). The data representing the contact surface S is stored in the main storage unit 22 and the external storage unit 23. Next, the electrostatic potential calculation unit 40 refers to the FMO method calculation program 29 stored in the main storage unit 22, the data representing the contact surface S, the three-dimensional structure data 2, and the data 31 representing the charge of molecule A, and calculates the partial electrostatic potential of molecule A at the contact surface S by removing the contribution of the charged amino acid residues (step S5). The data representing the partial electrostatic potential of molecule A is stored in the main storage unit 22 and the external storage unit 23.

[0163] Furthermore, the electrostatic potential calculation unit 50 refers to the FMO method calculation program 29, the data representing the contact surface S, the three-dimensional structure data 3, and the data 32 representing the charge of the molecule B stored in the main storage unit 22, removes the contribution of the charged amino acid residues, and calculates the partial electrostatic potential of the molecule B at the contact surface S (step S6). The intermolecular interaction analysis device 1 stores the data representing the partial electrostatic potential of the molecule B in the main storage unit 22 and the external storage unit 23, and ends the electrostatic potential evaluation process.

[0164] In addition, according to the user's instruction input via the operation unit 24, the CPU 21 can display an image in which the partial electrostatic potential of the molecule A and the partial electrostatic potential of the molecule B are plotted on the contact surface S on the display unit 25, or can calculate the above-mentioned ratio W － And displayed on the display unit 25.

[0165] The intermolecular interaction analysis device 1 according to the present embodiment calculates the partial electrostatic potential of molecule A at the contact surface S by removing the contribution of the charged amino acid residues corresponding to the charge when molecule A has a charge, and calculates the partial electrostatic potential of molecule B at the contact surface S by removing the contribution of the charged amino acid residues corresponding to the charge when molecule B has a charge. In this way, the original state of the partial electrostatic potential at the contact surface S can be evaluated by removing the influence of the overall charge. Thus, intermolecular interactions such as between proteins and between proteins and antibodies can be evaluated with high accuracy.

[0166] By accurately evaluating intermolecular interactions such as between proteins and between proteins and antibodies, antibodies can be designed to have a high degree of correspondence with the electrostatic potential of target proteins, thereby enabling efficient antibody development in a short period of time.

[0167] In addition, the contact surface definition unit 30 may define a surface where the partial electron density of molecule A is greater than a reference value as a contact surface S. When the surface where the partial electron density of molecule A is equal to the partial electron density of molecule B is infinitely extended, it is avoided that the portion where molecule A and molecule B do not interact is defined as a contact surface, so that the increase in the amount of calculation can be suppressed.

[0168] Implementation Method 2

[0169] Next, the second embodiment of the present invention will be described. The intermolecular interaction analysis device 5 as the information processing device according to this embodiment has the same hardware configuration as the intermolecular interaction analysis device 1 according to the first embodiment, but has a different software configuration. Figure 6 As shown, a dispersion force evaluation unit 60 is provided in place of the electrostatic potential calculation unit 40 and the electrostatic potential calculation unit 50 .

[0170] The dispersion force evaluation unit 60 evaluates the dispersion force based on the partial electron density of the molecule A and the partial electron density of the molecule B at the contact surface S. The dispersion force is a main component of the non-electrostatic interaction between the molecule A and the molecule B. The dispersion force increases approximately in proportion to the size of the induced dipole, that is, the size of the overlap of the partial electron density, so the dispersion force can be evaluated by quantifying the overlap of the partial electron density.

[0171] More specifically, the dispersion force evaluation unit 60 evaluates the dispersion force using an index representing the sum of the partial electron density of molecule A and the partial electron density of molecule B at the contact surface S, that is, the overlap of the partial electron density as an index. For example, as described in the first embodiment, when the electron density is calculated using three-dimensional mesh data, the dispersion force evaluation unit 60 obtains a value x obtained by multiplying the value of the partial electron density of molecule A and the value of the partial electron density of molecule B at each mesh grid at the contact surface S by a small area (the square of the length of one side of the mesh grid), and calculates the value (ρ) obtained by summing the values ​​x of each mesh grid. + ) is calculated as evaluation information 4. + It is an indicator of the overlap of partial electron density.

[0172] For example, Figure 7 ρ at the contact surface S of the complex of PD-1 and nivolumab is shown + ρ at the contact surface S + The total is 15.668. By calculating ρ +, it is possible to compare ρ between PD-1 and antibodies other than nivolumab or modified antibodies in which the prescribed amino acid residues of nivolumab are substituted. + .

[0173] Figure 6 The molecular interaction analysis device 5 shown in the figure is, for example, Figure 8 The main storage unit 22 is implemented by implementing a software program on a computer having the hardware configuration shown. The dispersion force evaluation program 33 is loaded from the external storage unit 23 instead of the electrostatic potential evaluation program 28 in the main storage unit 22. The dispersion force evaluation program 33 is pre-stored in the external storage unit 23 instead of the electrostatic potential evaluation program 28. In addition, the data 31 representing the charge of the molecule A and the data 32 representing the charge of the molecule B are not stored in the external storage unit 23.

[0174] Next, the intermolecular interaction analysis method realized by the operation of the intermolecular interaction analysis device 5 according to the present embodiment, that is, the dispersion force evaluation process executed by the intermolecular interaction analysis device 5 will be described.

[0175] First, the dispersion force evaluation program 33 is read from the external storage unit 23 into the main storage unit 22 , and the CPU 21 executes the dispersion force evaluation program 33 , thereby performing the dispersion force evaluation process.

[0176] like Fig. 9 As shown, for the dispersion force evaluation process, except that the data 31 representing the charge of molecule A and the data 32 representing the charge of molecule B are not read in step 1, steps 1 to S4 are the same as the electrostatic potential evaluation process in embodiment 1. After step 4, the dispersion force evaluation unit 60 refers to the data representing the contact surface S, the three-dimensional structure data 2, the three-dimensional structure data 3, the data representing the partial electron density of molecule A, and the data representing the partial electron density of molecule B stored in the main storage unit 22, and evaluates the dispersion force based on the partial electron density of molecule A and the partial electron density of molecule B at the contact surface S (step S7). The intermolecular interaction analysis device 5 stores the data representing the dispersion force in the main storage unit 22 and the external storage unit 23, and ends the dispersion force evaluation process.

[0177] The intermolecular interaction analysis device 5 according to the present embodiment evaluates dispersion force based on the partial electron density of molecule A and the partial electron density of molecule B at the contact surface S. In this way, non-electrostatic interactions, which are important in PPI, can be evaluated, so intermolecular interactions such as protein-protein and protein-antibody interactions can be evaluated with high accuracy.

[0178] Furthermore, the CPU 21 may display an image in which the dispersion force is plotted on the contact surface S on the display unit 25 in response to an instruction input from the user via the operation unit 24 .

[0179] The hardware configuration and software configuration of the above-mentioned intermolecular interaction analysis device 1 and intermolecular interaction analysis device 5 are merely examples and can be arbitrarily changed and modified.

[0180] The core part of the intermolecular interaction analysis device 1 and the intermolecular interaction analysis device 5, which is composed of the CPU 21, the main storage unit 22, the external storage unit 23, the operation unit 24, the display unit 25, the communication interface 26, and the internal bus 27, does not need a dedicated system, and can be implemented using a common computer system. For example, a computer program for executing the above-mentioned operations can be stored in a computer-readable recording medium (floppy disk, CD-ROM (compact disc read only memory) and DVD-ROM (digital versatile disk read only memory) etc.) and distributed, and the computer program can be installed in a computer, thereby configuring the intermolecular interaction analysis device 1 and the intermolecular interaction analysis device 5 that execute the above-mentioned processing. In addition, the computer program can be stored in advance in a storage device of a server device on a communication network such as the Internet, and can be downloaded from a common computer system to configure the intermolecular interaction analysis device 1 and the intermolecular interaction analysis device 5.

[0181] In addition, the intermolecular interaction analysis device 1 may further include a dispersion force evaluation unit 60. In this case, the intermolecular interaction analysis device 1 can calculate the partial electrostatic potential of molecule A and the partial electrostatic potential of molecule B at the contact surface S, and can also evaluate the dispersion force based on the partial electron density of molecule A and the partial electron density of molecule B at the contact surface S according to the user's instruction.

[0182] When the functions of the intermolecular interaction analysis device 1 and the intermolecular interaction analysis device 5 are realized by sharing the OS (operating system) and the application program, or by cooperation between the OS and the application program, only the application program portion may be stored in a recording medium or a storage device.

[0183] It is also possible to superimpose the computer program on a carrier wave and distribute it via a communication network. For example, the computer program may be published on a bulletin board (BBS, Bulletin Board System) on a communication network and distributed via the network. Furthermore, it is also possible to configure such that the above-mentioned processing can be performed by starting the computer program and executing it in the same manner as other application programs under the control of the OS.

[0184] According to the above-mentioned Embodiment 1 and Embodiment 2, the binding affinity (binding force) of PPI can be evaluated by quantifying electrostatic complementarity. Figure 1 The matching of the samples indicates a highly specific interaction, so it is possible to evaluate the specificity of PPI, which is difficult to perform using conventional computational techniques. Applications of this technology include, in addition to analyzing the contribution of each amino acid at a variable site to the affinity and specificity of the target protein, designing antibodies to increase the correspondence between the electrostatic potential and the target protein for the purpose of improving affinity and specificity, improving the stability of the antibody, etc.

[0185] The above-mentioned embodiments are used to illustrate the present invention and do not limit the scope of the present invention. That is, the scope of the present invention is not represented by the embodiments, but by the claims. Moreover, various modifications implemented within the claims and within the meaning of the invention equivalent thereto are considered to be within the scope of the present invention.

[0186] This application is based on Japanese Patent Application No. 2022-139395 filed on September 1, 2022. In this specification, the entire specification, claims, and drawings of Japanese Patent Application No. 2022-139395 are incorporated herein by reference.

[0187] Industrial Applicability

[0188] The present invention is useful for analyzing the interaction between proteins or between proteins and antibodies.

[0189] Description of Reference Numerals

[0190] 1, 5 intermolecular interaction analysis device; 2, 3 three-dimensional structure data; 4 evaluation information; 10, 20 electron density calculation unit; 30 contact surface definition unit; 40, 50 electrostatic potential calculation unit; 60 dispersion force evaluation unit; 21 CPU; 22 main storage unit; 23 external storage unit; 24 operation unit; 25 display unit; 26 communication interface; 27 internal bus; 28 electrostatic potential evaluation program; 29 FMO method calculation program; 31 data representing the charge of molecule A; 32 data representing the charge of molecule B; 33 dispersion force evaluation program.

Claims

1. A molecular interaction analysis device comprising: A first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds; a second electron density calculation unit, for calculating partial electron density of the second molecule by a fragment molecular orbital method based on three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position interacting with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds; a contact surface defining unit, defining a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface; a first electrostatic potential calculation unit that, when the first molecule has a charge, removes a contribution of a charged amino acid residue corresponding to the charge of the first molecule and calculates a partial electrostatic potential of the first molecule at the contact surface by a fragment molecular orbital method; and The second electrostatic potential calculation unit calculates the partial electrostatic potential of the second molecule at the contact surface by a fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the second molecule, when the second molecule has a charge.

2. The molecular interaction analysis device according to claim 1, wherein: The contact surface defining unit defines a surface where the partial electron density of the first molecule is greater than or equal to a reference value as the contact surface.

3. The molecular interaction analysis device according to claim 1 or 2, wherein: The first electrostatic potential calculation unit is: In the case where the first molecule has a positive charge of +n, n arginine residues and lysine residues contained in the first molecule are selected in descending order of distance from the contact surface as the charged amino acid residues, and the partial electrostatic potential of the entire first molecule is calculated by removing the selected charged amino acid residues. In the case where the first molecule has a negative charge of -n, n aspartic acid and glutamic acid residues contained in the first molecule are selected in descending order of distance from the contact surface as the charged amino acid residues, and the partial electrostatic potential of the entire first molecule is calculated by removing the selected charged amino acid residues. The second electrostatic potential calculation unit is: In the case where the second molecule has a positive charge of +n, n arginine residues and lysine residues contained in the second molecule are selected in descending order of distance from the contact surface as the charged amino acid residues, and the partial electrostatic potential of the second molecule as a whole is calculated by removing the selected charged amino acid residues. When the second molecule has a negative charge of -n, n aspartic acid and glutamic acid residues contained in the second molecule are selected in descending order of distance from the contact surface as the charged amino acid residues, and the partial electrostatic potential of the selected charged amino acid residues is removed to calculate the partial electrostatic potential of the second molecule as a whole.

4. A molecular interaction analysis device comprising: A first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds; a second electron density calculation unit, for calculating partial electron density of the second molecule by a fragment molecular orbital method based on three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position interacting with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds; a contact surface defining unit that defines a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface; and The dispersion force evaluation unit evaluates the dispersion force based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

5. The molecular interaction analysis device according to claim 4, wherein: The contact surface defining unit defines a surface where the partial electron density of the first molecule is greater than or equal to a reference value as the contact surface.

6. The molecular interaction analysis device according to claim 4 or 5, wherein: The dispersion force evaluation unit evaluates the dispersion force using an index indicating an overlap of a partial electron density calculated from a sum of a partial electron density of the first molecule and a partial electron density of the second molecule at the contact surface as the dispersion force.

7. A molecular interaction analysis device comprising: A first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds; a second electron density calculation unit, for calculating partial electron density of the second molecule by a fragment molecular orbital method based on three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position interacting with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds; a contact surface defining unit, defining a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface; a first electrostatic potential calculation unit, which, when the first molecule has a charge, removes a contribution of a charged amino acid residue corresponding to the charge of the first molecule and calculates a partial electrostatic potential of the first molecule at the contact surface by a fragment molecular orbital method; a second electrostatic potential calculation unit that, when the second molecule has a charge, removes a contribution of a charged amino acid residue corresponding to the charge of the second molecule and calculates a partial electrostatic potential of the second molecule at the contact surface by a fragment molecular orbital method; and The dispersion force evaluation unit evaluates the dispersion force based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

8. A method for analyzing molecular interactions, comprising: Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds; calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds; A surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule is defined as a contact surface; When the first molecule has a charge, the partial electrostatic potential of the first molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the first molecule; When the second molecule has a charge, the partial electrostatic potential of the second molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residue corresponding to the charge of the second molecule.

9. A method for analyzing molecular interactions, comprising: Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds; calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds; defining a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface; and The dispersion force is evaluated based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

10. A method for analyzing molecular interactions, comprising: Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds; calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds; A surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule is defined as a contact surface; When the first molecule has a charge, the partial electrostatic potential of the first molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the first molecule; When the second molecule has a charge, the partial electrostatic potential of the second molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the second molecule; and The dispersion force is evaluated based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

11. A program that causes a computer to function as a first electron density calculation unit, a second electron density calculation unit, a contact surface definition unit, a first electrostatic potential calculation unit, and a second electrostatic potential calculation unit, The first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds. The second electron density calculation unit calculates partial electron density of the second molecule by a fragment molecular orbital method for three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and includes a plurality of amino acid residues bonded via peptide bonds, The contact surface defining unit defines a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface, The first electrostatic potential calculation unit calculates the partial electrostatic potential of the first molecule at the contact surface by a fragment molecular orbital method, removing the contribution of the charged amino acid residues corresponding to the charge of the first molecule when the first molecule has a charge. When the second molecule has a charge, the second electrostatic potential calculation unit calculates the partial electrostatic potential of the second molecule at the contact surface by a fragment molecular orbital method, excluding a contribution of a charged amino acid residue corresponding to the charge of the second molecule.

12. A program that causes a computer to function as a first electron density calculation unit, a second electron density calculation unit, a contact surface definition unit, and a dispersion force evaluation unit, The first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds. The second electron density calculation unit calculates partial electron density of the second molecule by a fragment molecular orbital method for three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and includes a plurality of amino acid residues bonded via peptide bonds, The contact surface defining unit defines a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface, The dispersion force evaluation unit evaluates the dispersion force based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

13. A program that causes a computer to function as a first electron density calculation unit, a second electron density calculation unit, a contact surface definition unit, a first electrostatic potential calculation unit, a second electrostatic potential calculation unit, and a dispersion force evaluation unit, The first electron density calculation unit calculates partial electron density of the first molecule by a fragment molecular orbital method based on three-dimensional structural data of the first molecule, wherein the first molecule includes a plurality of amino acid residues bonded via peptide bonds. The second electron density calculation unit calculates partial electron density of the second molecule by a fragment molecular orbital method for three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and includes a plurality of amino acid residues bonded via peptide bonds, The contact surface defining unit defines a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface, The first electrostatic potential calculation unit calculates the partial electrostatic potential of the first molecule at the contact surface by a fragment molecular orbital method, removing the contribution of the charged amino acid residues corresponding to the charge of the first molecule when the first molecule has a charge. The second electrostatic potential calculation unit calculates the partial electrostatic potential of the second molecule at the contact surface by a fragment molecular orbital method, removing the contribution of the charged amino acid residues corresponding to the charge of the second molecule when the second molecule has a charge. The dispersion force evaluation unit evaluates the dispersion force based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

14. A molecular interaction analysis device comprising: Memory, which stores programs; and The CPU (central processing unit) reads the above program from the above memory and executes it. The above CPU performs the following processing: Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds; calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds; A surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule is defined as a contact surface; When the first molecule has a charge, excluding the contribution of the charged amino acid residues corresponding to the charge of the first molecule, the partial electrostatic potential of the first molecule at the contact surface is calculated by the fragment molecular orbital method; and When the second molecule has a charge, the partial electrostatic potential of the second molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residue corresponding to the charge of the second molecule.

15. A molecular interaction analysis device comprising: Memory, which stores programs; and The CPU (central processing unit) reads the above program from the above memory and executes it. The above CPU performs the following processing: Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds; calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds; defining a surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule as a contact surface; and The dispersion force is evaluated based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

16. A molecular interaction analysis device comprising: Memory, which stores programs; and The CPU (central processing unit) reads the above program from the above memory and executes it. The above CPU performs the following processing: Calculating partial electron density of the first molecule by a fragment molecular orbital method based on the three-dimensional structural data of the first molecule, wherein the first molecule comprises a plurality of amino acid residues bonded via peptide bonds; calculating partial electron density of the second molecule by a fragment molecular orbital method for the three-dimensional structural data of the second molecule, wherein the second molecule is arranged at a position that interacts with the first molecule relative to the first molecule and comprises a plurality of amino acid residues bonded via peptide bonds; A surface where the partial electron density of the first molecule is equal to the partial electron density of the second molecule is defined as a contact surface; When the first molecule has a charge, the partial electrostatic potential of the first molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the first molecule; When the second molecule has a charge, the partial electrostatic potential of the second molecule at the contact surface is calculated by the fragment molecular orbital method, excluding the contribution of the charged amino acid residues corresponding to the charge of the second molecule; and The dispersion force is evaluated based on the partial electron density of the first molecule and the partial electron density of the second molecule at the contact surface.

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