A method and system for calculating the solvation free energy of drug molecules

Abstract

The present invention relates to the technical field of computer-aided drug design, and in particular to a method and system for calculating the solvation free energy of drug molecules. The present invention evaluates the solute-solvent interaction at the atomic level by calculating the non-bonded interaction between each solute atom and a water molecule. To increase the calculation speed, an outwardly extending water solvent layer is constructed outside the solute molecule. The solvation free energy of the solute molecule is predicted by calculating the interaction energy between each atom in the solute molecule and the solvent layer, thereby realizing accurate simulation of the free energy of the dissolution process of the drug molecule.

Description

Technical Field

[0001] The present invention relates to the technical field of computer-aided drug design, and in particular to a method and system for calculating the solvation free energy of drug molecules. Background Art

[0002] For many years, the development of predictive algorithms for the solvation capacity of drug molecules has always aroused great interest. The main reason is that most drugs occur in an aqueous environment during absorption, diffusion and transport in the body, and the exertion of their efficacy. In recent years, through experimental and computational studies on the water structure and solvation free energy around organic and biological molecular solutes, we have provided a large amount of physical and chemical information related to the solvation process of drug-like molecules, which provides good data support for the development of accurate algorithms for the solvation free energy of drug molecules. Accurate simulation of the solubility of drug molecules is an important research direction in computer-aided drug design. Summary of the invention

[0003] In view of the above-mentioned deficiencies of the prior art, the present invention aims to provide a method and system for calculating the solvation free energy of drug molecules, so as to realize the free energy calculation of drug molecules and solvent molecules in the solvation process and the accurate simulation of the free energy of the dissolution process of drug molecules.

[0004] In order to solve the above problems, the present invention adopts the following technical solutions:

[0005] The semi-continuous water molecule model is used to calculate the solvation free energy. The solute-solvent interaction at the atomic level is evaluated by calculating the non-bonded interaction between each solute atom and the water molecule. To increase the computational speed, an extended water solvent layer is constructed outside the solute molecule, and the solvation free energy of the solute molecule is predicted by calculating the interaction energy between each atom in the solute molecule and the solvent layer.

[0006] In one aspect, the present invention provides a method for calculating the solvation free energy of a drug molecule, comprising:

[0007] The drug molecules and water are simulated as solute molecules and solvent layers, and the continuous solvent layer is evenly distributed outside the solute molecules;

[0008] The number of water molecules in each solvent layer is calculated by the maximum cross-sectional area of ​​water molecules and the accessible surface area of ​​solvent molecules in each solvent layer;

[0009] Based on the calculation of the number of water molecules in each solvent layer, the TIP3P model is used to construct a water molecule model in each solvent layer, and the Amber force field is used to calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule, and then the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule is calculated;

[0010] According to the interaction potential between the three atoms in the water molecules in each solvent layer and each atom in the solute molecule, a local partition function of the interaction between the water molecules in each solvent layer and the solute atoms is generated, and the partition function of the interaction between the water molecules in each solvent layer and the solute atoms is obtained. Then, the total partition function of the interaction between all solute atoms in each solvent layer is calculated to obtain the solute-solvent partition function.

[0011] The free energy change caused by solute-solvent interaction is calculated based on the mathematical relationship between the solute-solvent partition function and the free energy.

[0012] As an implementation method, the number of water molecules in each solvent layer is Calculated by the following formula:

[0013]

[0014] in, is the accessible surface area of ​​solvent molecules in each solvent layer, is the maximum cross-sectional area of ​​a water molecule; the maximum cross-sectional area of ​​a water molecule By calculating the square of the radius of the water molecule multiplied by The accessible surface area of ​​solvent molecules in each solvent layer is calculated by preserving the grid space method.

[0015] As an implementation method, the accessible surface area of ​​the solvent molecules of each solvent layer is calculated by retaining the grid space method and includes:

[0016] For the distance from the center of the solute atom in the solute molecule The solvent layers will have equal spacing And uniformly distributed grid points are placed around each solute atom;

[0017] The distance from the center of the solute atom Distance in All grid points outside the range are deleted, generating a circle with a distance of , thickness is The grid point sphere shell;

[0018] The grid points that collide with the entire solute molecular structure are excluded, and the grid points in the spherical shell of the grid points are further deleted;

[0019] For the remaining grid points, it is used to represent The spatial coordinates of the solvent layer, the The accessible surface area of ​​the solvent molecules of the solvent layer is calculated by the following formula:

[0020]

[0021] in, is the number of remaining grid points, is the standard surface area occupied by each grid point.

[0022] As an implementable method, the method of constructing a water molecule model in each solvent layer using the TIP3P model based on calculating the number of water molecules in each solvent layer includes:

[0023] With each atom in the solute molecule as the center, the radius is Construct the solvent layer and place water molecules in each layer using the TIP3P model as geometric parameters. In the solvent layer, the conformation of water molecules is constructed;

[0024] For each water molecule, a spherical shell grid lattice is generated with the oxygen atom as the center and the oxygen-hydrogen atom bond length as the radius. The spacing between the grid points of the spherical shell grid lattice is 0.1 Å;

[0025] Place any one of the two hydrogen atoms in the water molecule on each grid point in the spherical shell grid lattice, and based on the geometric positions of oxygen and hydrogen atoms, place the other hydrogen atom on a grid point that satisfies the angle formed by the hydrogen, oxygen and hydrogen atoms of 104.52°;

[0026] The positions of the two hydrogen atoms were searched and the degenerate state caused by the two equivalent hydrogen atoms in the TIP3P water molecule was excluded to construct the conformations of all TIP3P water molecules in the R-layer solvent layer.

[0027] As an implementable method, the use of the Amber force field to calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule, and then calculating the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule includes:

[0028] The interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule is calculated using the following formula: :

[0029]

[0030]

[0031]

[0032]

[0033] Among them, A O-i is the repulsion coefficient between oxygen atom O and solute atom i, A H1-i is the repulsive force coefficient between hydrogen atom H1 and solute atom i, AH2-i is the repulsive force coefficient between another hydrogen atom H2 and solute atom i; B O-i is the attraction coefficient between oxygen atom O and solute atom i, B H1-i is the attraction coefficient between hydrogen atom H1 and solute atom i, B H2-i is the attraction coefficient between another hydrogen atom H2 and solute atom i; r O-i is the distance between oxygen atom O and solute atom i, r H1-i is the distance between hydrogen atom H1 and solute atom i, r H2-i is the distance between hydrogen atom H2 and solute atom i; q O is the charge of the oxygen atom O, q i is the charge of solute atom i, q H1 is the charge of hydrogen atom H1, q H2 is the charge of another hydrogen atom H2; is the interaction potential energy between oxygen atom O and solute atom i, is the interaction potential energy between hydrogen atom H1 and solute atom i, is the interaction potential energy between another hydrogen atom H2 and solute atom i;

[0034] The interaction potential energy between the three atoms in all water molecules in the solvent layer and each atom in the solute molecule is added together to obtain the interaction potential energy between the three atoms in the water molecules in each solvent layer and each atom in the solute molecule.

[0035] As an implementation method, the local partition function of the interaction between water molecules in each solvent layer and solute atoms is Calculated by the following formula:

[0036]

[0037] in, is the kth TIP3P water conformation, For TIP3P water molecules The total number of conformations in the solvent layer, i is the solute atom, is the product of the gas constant and the body temperature;

[0038] The local partition function of the interaction between water molecules and solute atoms in each solvent layer is calculated by the following formula: :

[0039] ;

[0040] The local partition function of the interaction between water molecules and solute atoms in each solvent layer is integrated to obtain the total partition function of each solvent layer for the interaction of all solute atoms. ,

[0041]

[0042] Among them, N i is the total number of solute atoms;

[0043] The solvent layer wraps around the solute molecule in 0.1 Å increments, starting from the water accessible surface of the solute molecule and ending at 20 Å from the geometric center of each atom of the solute molecule. The solute-solvent partition function for:

[0044]

[0045] in, The index number of the specific solvent layer, is the number of total solvent layers extending 20 Å from the van der Waals radius of the solute atom to the open space.

[0046] As an implementation method, the mathematical relationship between the solute-solvent partition function and the free energy is:

[0047]

[0048] in, is the solute-solvent free energy.

[0049] On the other hand, the present invention provides a solvation free energy calculation system for drug molecules, comprising a simulation module, a water molecule quantity calculation module, an interaction potential energy calculation module, a solute-solvent partition function calculation module and a free energy change calculation module;

[0050] The simulation module is used to simulate drug molecules and water as solute molecules and solvent layers, and the continuous solvent layer is evenly distributed outside the solute molecules;

[0051] The water molecule number calculation module is used to calculate the number of water molecules in each solvent layer according to the maximum cross-sectional area of ​​the water molecules and the accessible surface area of ​​the solvent molecules in each solvent layer;

[0052] The interaction potential energy calculation module is used to calculate the number of water molecules in each solvent layer, construct a water molecule model in each solvent layer using the TIP3P model, calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule using the Amber force field, and then calculate the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule;

[0053] The solute-solvent partition function calculation module is used to generate a local partition function of the interaction between water molecules and solute atoms in each solvent layer according to the interaction potential between three atoms in the water molecules in each solvent layer and each atom in the solute molecule, obtain the partition function of the interaction between water molecules and solute atoms in each solvent layer, and then calculate the total partition function of each solvent layer for the interaction of all solute atoms to obtain the solute-solvent partition function;

[0054] The free energy change calculation module is used to calculate the free energy change caused by the solute-solvent interaction according to the mathematical relationship between the solute-solvent partition function and the free energy.

[0055] As an implementation method, the number of water molecules in each solvent layer is Calculated by the following formula:

[0056]

[0057] in, is the accessible surface area of ​​solvent molecules in each solvent layer, is the maximum cross-sectional area of ​​a water molecule; the maximum cross-sectional area of ​​a water molecule By calculating the square of the radius of the water molecule multiplied by The accessible surface area of ​​solvent molecules in each solvent layer is calculated by preserving the grid space method.

[0058] As an implementation method, the accessible surface area of ​​the solvent molecules of each solvent layer is calculated by retaining the grid space method and includes:

[0059] For the distance from the center of the solute atom in the solute molecule The solvent layers will have equal spacing And uniformly distributed grid points are placed around each solute atom;

[0060] The distance from the center of the solute atom Distance in All grid points outside the range are deleted, generating a circle with a distance of , thickness is The grid point sphere shell;

[0061] The grid points that collide with the entire solute molecular structure are excluded, and the grid points in the spherical shell of the grid points are further deleted;

[0062] For the remaining grid points, it is used to represent The spatial coordinates of the solvent layer, the The accessible surface area of ​​the solvent molecules of the solvent layer is calculated by the following formula:

[0063]

[0064] in, is the number of remaining grid points, is the standard surface area occupied by each grid point.

[0065] As an implementable method, the method of constructing a water molecule model in each solvent layer using the TIP3P model based on calculating the number of water molecules in each solvent layer includes:

[0066] With each atom in the solute molecule as the center, the radius is Construct the solvent layer and place water molecules in each layer using the TIP3P model as geometric parameters. In the solvent layer, the conformation of water molecules is constructed;

[0067] For each water molecule, a spherical shell grid lattice is generated with the oxygen atom as the center and the oxygen-hydrogen atom bond length as the radius. The spacing between the grid points of the spherical shell grid lattice is 0.1 Å;

[0068] Place any one of the two hydrogen atoms in the water molecule on each grid point in the spherical shell grid lattice, and based on the geometric positions of oxygen and hydrogen atoms, place the other hydrogen atom on a grid point that satisfies the angle formed by the hydrogen, oxygen and hydrogen atoms of 104.52°;

[0069] The positions of the two hydrogen atoms were searched and the degenerate state caused by the two equivalent hydrogen atoms in the TIP3P water molecule was excluded to construct the conformations of all TIP3P water molecules in the R-layer solvent layer.

[0070] As an implementable method, the use of the Amber force field to calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule, and then calculating the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule includes:

[0071] The interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule is calculated using the following formula: :

[0072]

[0073]

[0074]

[0075]

[0076] Among them, A O-i is the repulsion coefficient between oxygen atom O and solute atom i, A H1-iis the repulsive force coefficient between hydrogen atom H1 and solute atom i, A H2-i is the repulsive force coefficient between another hydrogen atom H2 and solute atom i; B O-i is the attraction coefficient between oxygen atom O and solute atom i, B H1-i is the attraction coefficient between hydrogen atom H1 and solute atom i, B H2-i is the attraction coefficient between another hydrogen atom H2 and solute atom i; r O-i is the distance between oxygen atom O and solute atom i, r H1-i is the distance between hydrogen atom H1 and solute atom i, r H2-i is the distance between hydrogen atom H2 and solute atom i; q O is the charge of the oxygen atom O, q i is the charge of solute atom i, q H1 is the charge of hydrogen atom H1, q H2 is the charge of another hydrogen atom H2; is the interaction potential energy between oxygen atom O and solute atom i, is the interaction potential energy between hydrogen atom H1 and solute atom i, is the interaction potential energy between another hydrogen atom H2 and solute atom i;

[0077] The interaction potential energy between the three atoms in all water molecules in the solvent layer and each atom in the solute molecule is added together to obtain the interaction potential energy between the three atoms in the water molecules in each solvent layer and each atom in the solute molecule.

[0078] As an implementation method, the local partition function of the interaction between water molecules in each solvent layer and solute atoms is Calculated by the following formula:

[0079]

[0080] in, is the kth TIP3P water conformation, For TIP3P water molecules The total number of conformations in the solvent layer, i is the solute atom, is the product of the gas constant and the body temperature;

[0081] The local partition function of the interaction between water molecules and solute atoms in each solvent layer is calculated by the following formula: :

[0082] ;

[0083] The local partition function of the interaction between water molecules and solute atoms in each solvent layer is integrated to obtain the total partition function of each solvent layer for the interaction of all solute atoms. ,

[0084]

[0085] Among them, N i is the total number of solute atoms;

[0086] The solvent layer wraps around the solute molecule in 0.1 Å increments, starting from the water accessible surface of the solute molecule and ending at 20 Å from the geometric center of each atom of the solute molecule. The solute-solvent partition function for:

[0087]

[0088] in, The index number of the specific solvent layer, is the number of total solvent layers extending 20 Å from the van der Waals radius of the solute atom to the open space.

[0089] As an implementation method, the mathematical relationship between the solute-solvent partition function and the free energy is:

[0090]

[0091] in, is the solute-solvent free energy.

[0092] The beneficial effects of the present invention are as follows: the present invention evaluates the solute-solvent interaction at the atomic level by calculating the non-bonded interaction between each solute atom and the water molecule, constructs an outwardly extending water solvent layer outside the solute molecule to increase the calculation speed, and predicts the solvation free energy of the solute molecule by calculating the interaction energy between each atom in the solute molecule and the solvent layer, thereby achieving accurate simulation of the free energy of the dissolution process of the drug molecule. BRIEF DESCRIPTION OF THE DRAWINGS

[0093] Figure 1 The figure is a flow chart of a method for calculating the solvation free energy of a drug molecule in an embodiment of the present invention.

[0094] Figure 2 Schematic diagram of constructing a solvent layer outside the solute molecules in an embodiment of the present invention.

[0095] Figure 3 Schematic diagram of a solvation free energy calculation system for a drug molecule in an embodiment of the present invention. DETAILED DESCRIPTION

[0096] The present invention is further described in detail below in conjunction with specific embodiments.

[0097] It should be noted that these embodiments are only used to illustrate the present invention rather than to limit the present invention. Simple improvements to the method based on the concept of the present invention all fall within the scope of protection claimed by the present invention.

[0098] Example 1

[0099] See also Figure 1 , a method for calculating the solvation free energy of drug molecules, including:

[0100] S100, drug molecules and water are simulated as solute molecules and solvent layers, and the continuous solvent layer is evenly distributed outside the solute molecules.

[0101] A series of continuously distributed volume space layers are established around the solute, and each space layer is set as a solvent layer that wraps the solute molecules. Each solvent layer is composed of several spherical shells, and each spherical shell is distributed around the center of each solute atom at a radius of R from the geometric center of the corresponding solute atom, so each solvent layer is equivalent to a thin layer of water uniformly distributed at a distance R from the outside of the solute molecule.

[0102] S200, calculating the number of water molecules in each solvent layer by the maximum cross-sectional area of ​​water molecules and the accessible surface area of ​​solvent molecules in each solvent layer.

[0103] The number of water molecules in each solvent layer is calculated by comparing the maximum cross-sectional area of ​​water molecules with the solvent accessible surface area of ​​each solvent layer. That is, the accessible surface area of ​​solvent molecules in solvent layer R ( ) and the maximum cross-sectional area of ​​a water molecule ( ) ratio, calculate the distance from the geometric center of the solute atom to each atom on the R layer that can be reached Number of water molecules .

[0104] Then, the number of water molecules in each solvent layer is Calculated by the following formula:

[0105]

[0106] in, is the accessible surface area of ​​solvent molecules in each solvent layer, is the maximum cross-sectional area of ​​a water molecule; the maximum cross-sectional area of ​​a water molecule By calculating the square of the radius of the water molecule multiplied by The accessible surface area of ​​solvent molecules in each solvent layer is calculated by preserving the grid space method.

[0107] The maximum cross-sectional area of ​​a water molecule By calculating the radius of a water molecule (1.6 angstroms) squared and multiplying To obtain:

[0108] .

[0109] Accessible surface area of ​​each solvent layer Calculated using the grid space preservation method, including:

[0110] For the distance from the center of the solute atom in the solute molecule The solvent layers will have equal spacing And uniformly distributed grid points are placed around each solute atom;

[0111] The distance from the center of the solute atom Distance in All grid points outside the range are deleted, generating a circle with a distance of , thickness is The grid point sphere shell;

[0112] The grid points that collide with the entire solute molecular structure are excluded, and the grid points in the spherical shell of the grid points are further deleted;

[0113] For the remaining grid points, it is used to represent The spatial coordinates of the solvent layer, the The accessible surface area of ​​the solvent molecules of the solvent layer is calculated by the following formula:

[0114]

[0115] in, is the number of remaining grid points, is the standard surface area occupied by each grid point.

[0116] S300, based on calculating the number of water molecules in each solvent layer, uses the TIP3P model to construct a water molecule model in each solvent layer, uses the Amber force field to calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule, and then calculates the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule.

[0117] The parameter set of the TIP3P water molecule model is shown in Table 1.

[0118] Table 1. Parameter set of TIP3P water molecule model.

[0119] For each water molecule j in any solvent layer, the geometric center of the oxygen atom in it remains on the solvent layer, and the distance between the oxygen atom and the solute atom i is calculated as The geometric center of oxygen was used as the rotation center to sample all hydrogen geometries by rotating the water molecule and perform the solvation free energy calculation of the solute molecule.

[0120] The two hydrogens in water are rotated during the sampling process while maintaining the relative HOH geometry in the TIP3P water molecule model. The grid space points are used again to calculate the distribution of the two hydrogens centered on the oxygen atom. For each water molecule, the method first generates a spherical shell grid lattice with the oxygen atom (defined as O) as the center and the oxygen-hydrogen atom bond length as the radius. The grid lattice uses 0.1 Å as the spacing between grid points. Then, any one of the two hydrogen atoms in the water molecule (defined as H1) is placed on each grid point in the spherical shell grid lattice, and based on the geometric positions of the two atoms O and H1 and the TIP3P water molecule parameters, the position of the second hydrogen atom H2 is searched, and for each possible set of H1-O-H2 molecular conformations with the O atom as the geometric center, the interaction energy between each atom in the solute and the water molecule is calculated.

[0121] For details, see Figure 2 , Based on calculating the number of water molecules in each solvent layer, the TIP3P model is used to construct a water molecule model in each solvent layer, including:

[0122] With each atom in the solute molecule as the center, the radius is Construct the solvent layer and place water molecules in each layer using the TIP3P model as geometric parameters. In the solvent layer, the water molecule conformation is constructed.

[0123] For each water molecule, a spherical shell grid lattice is generated with the oxygen atom as the center and the oxygen-hydrogen atom bond length as the radius. The spacing between the grid points of the spherical shell grid lattice is 0.1 Å.

[0124] Place any one of the two hydrogen atoms in the water molecule on each grid point in the spherical shell grid lattice, and based on the geometric positions of the oxygen and hydrogen atoms, place the other hydrogen atom on a grid point that satisfies the angle formed by the hydrogen, oxygen and hydrogen atoms of 104.52°.

[0125] The positions of the two hydrogen atoms were searched and the degenerate state caused by the two equivalent hydrogen atoms in the TIP3P water molecule was excluded to construct the conformations of all TIP3P water molecules in the R-layer solvent layer.

[0126] Then, the Amber force field is used to calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule, and then the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule is calculated, including:

[0127] The interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule is calculated using the following formula: :

[0128]

[0129]

[0130]

[0131]

[0132] Among them, A O-i is the repulsion coefficient between oxygen atom O and solute atom i, A H1-i is the repulsive force coefficient between hydrogen atom H1 and solute atom i, A H2-i is the repulsive force coefficient between another hydrogen atom H2 and solute atom i; B O-i is the attraction coefficient between oxygen atom O and solute atom i, B H1-i is the attraction coefficient between hydrogen atom H1 and solute atom i, B H2-i is the attraction coefficient between another hydrogen atom H2 and solute atom i; r O-i is the distance between oxygen atom O and solute atom i, r H1-i is the distance between hydrogen atom H1 and solute atom i, r H2-i is the distance between hydrogen atom H2 and solute atom i; q O is the charge of the oxygen atom O, q i is the charge of solute atom i, q H1 is the charge of hydrogen atom H1, q H2 is the charge of another hydrogen atom H2; is the interaction potential energy between oxygen atom O and solute atom i, is the interaction potential energy between hydrogen atom H1 and solute atom i, is the interaction potential energy between another hydrogen atom H2 and solute atom i.

[0133] The interaction potential energy between the three atoms in all water molecules in the solvent layer and each atom in the solute molecule is added together to obtain the interaction potential energy between the three atoms in the water molecules in each solvent layer and each atom in the solute molecule.

[0134] S400, based on the interaction potential between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule Generate local partition functions for the interaction between water molecules and solute atoms in each solvent layer , and obtain the partition function of the interaction between water molecules and solute atoms in each solvent layer , and then calculate the total partition function of each solvent layer for the interaction of all solute atoms , and the solute-solvent partition function is obtained .

[0135] The present invention provides a specific implementation method of the above process:

[0136] The local partition function of the interaction between water molecules and solute atoms in each solvent layer Calculated by the following formula:

[0137]

[0138] in, is the kth TIP3P water conformation, For TIP3P water molecules The total number of conformations in the solvent layer, i is the solute atom, is the product of the gas constant and the body temperature;

[0139] The local partition function of the interaction between water molecules and solute atoms in each solvent layer is calculated by the following formula: :

[0140] ;

[0141] The local partition function of the interaction between water molecules and solute atoms in each solvent layer is integrated to obtain the total partition function of each solvent layer for the interaction of all solute atoms. ,

[0142]

[0143] Among them, N i is the total number of solute atoms;

[0144] The solvent layer wraps around the solute molecule in 0.1 Å increments, starting from the water accessible surface of the solute molecule and ending at 20 Å from the geometric center of each atom of the solute molecule. The solute-solvent partition function for:

[0145]

[0146] in, The index number of the specific solvent layer, is the number of total solvent layers extending 20 Å from the van der Waals radius of the solute atom to the open space.

[0147] S500, calculating the free energy change caused by the solute-solvent interaction according to the mathematical relationship between the solute-solvent partition function and the free energy.

[0148] The mathematical relationship between the solute-solvent partition function and free energy is:

[0149]

[0150] in, is the solute-solvent free energy.

[0151] Example 2

[0152] See also Figure 3 , which is a solvation free energy calculation system for drug molecules, including a simulation module 100, a water molecule number calculation module 200, an interaction potential energy calculation module 300, a solute-solvent partition function calculation module 400 and a free energy change calculation module 500.

[0153] The simulation module 100 is used to simulate drug molecules and water as solute molecules and solvent layers, and the continuous solvent layer is evenly distributed outside the solute molecules.

[0154] The water molecule number calculation module 200 is used to calculate the number of water molecules in each solvent layer according to the maximum cross-sectional area of ​​the water molecules and the accessible surface area of ​​the solvent molecules in each solvent layer.

[0155] Specifically, the number of water molecules in each solvent layer Calculated by the following formula:

[0156]

[0157] in, is the accessible surface area of ​​solvent molecules in each solvent layer, is the maximum cross-sectional area of ​​a water molecule; the maximum cross-sectional area of ​​a water molecule By calculating the square of the radius of the water molecule multiplied by The accessible surface area of ​​solvent molecules in each solvent layer is calculated by preserving the grid space method.

[0158] The accessible surface area of ​​each solvent layer is calculated by preserving the grid space method and includes:

[0159] For the distance from the center of the solute atom in the solute molecule The solvent layers will have equal spacing And uniformly distributed grid points are placed around each solute atom;

[0160] The distance from the center of the solute atom Distance in All grid points outside the range are deleted, generating a circle with a distance of , thickness is The grid point sphere shell;

[0161] The grid points that collide with the entire solute molecular structure are excluded, and the grid points in the spherical shell of the grid points are further deleted;

[0162] For the remaining grid points, it is used to represent The spatial coordinates of the solvent layer, the The accessible surface area of ​​the solvent molecules of the solvent layer is calculated by the following formula:

[0163]

[0164] in, is the number of remaining grid points, is the standard surface area occupied by each grid point.

[0165] The interaction potential energy calculation module 300 is used to calculate the number of water molecules in each solvent layer, construct a water molecule model in each solvent layer using the TIP3P model, calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule using the Amber force field, and then calculate the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule.

[0166] Specifically, based on calculating the number of water molecules in each solvent layer, constructing a water molecule model using the TIP3P model in each solvent layer includes:

[0167] With each atom in the solute molecule as the center, the radius is Construct the solvent layer and place water molecules in each layer using the TIP3P model as geometric parameters. In the solvent layer, the water molecule conformation is constructed.

[0168] For each water molecule, a spherical shell grid lattice is generated with the oxygen atom as the center and the oxygen-hydrogen atom bond length as the radius. The spacing between the grid points of the spherical shell grid lattice is 0.1 Å.

[0169] Place any one of the two hydrogen atoms in the water molecule on each grid point in the spherical shell grid lattice, and based on the geometric positions of the oxygen and hydrogen atoms, place the other hydrogen atom on a grid point that satisfies the angle formed by the hydrogen, oxygen and hydrogen atoms of 104.52°.

[0170] The positions of the two hydrogen atoms were searched and the degenerate state caused by the two equivalent hydrogen atoms in the TIP3P water molecule was excluded to construct the conformations of all TIP3P water molecules in the R-layer solvent layer.

[0171] Specifically, the Amber force field is used to calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule, and then the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule is calculated, including:

[0172] The interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule is calculated using the following formula: :

[0173]

[0174]

[0175]

[0176]

[0177] Among them, A O-i is the repulsion coefficient between oxygen atom O and solute atom i, A H1-i is the repulsive force coefficient between hydrogen atom H1 and solute atom i, A H2-i is the repulsive force coefficient between another hydrogen atom H2 and solute atom i; B O-i is the attraction coefficient between oxygen atom O and solute atom i, B H1-i is the attraction coefficient between hydrogen atom H1 and solute atom i, B H2-i is the attraction coefficient between another hydrogen atom H2 and solute atom i; r O-i is the distance between oxygen atom O and solute atom i, r H1-i is the distance between hydrogen atom H1 and solute atom i, r H2-i is the distance between hydrogen atom H2 and solute atom i; q O is the charge of the oxygen atom O, q i is the charge of solute atom i, q H1 is the charge of hydrogen atom H1, q H2 is the charge of another hydrogen atom H2; is the interaction potential energy between oxygen atom O and solute atom i, is the interaction potential energy between hydrogen atom H1 and solute atom i, is the interaction potential energy between another hydrogen atom H2 and solute atom i;

[0178] The interaction potential energy between the three atoms in all water molecules in the solvent layer and each atom in the solute molecule is added together to obtain the interaction potential energy between the three atoms in the water molecules in each solvent layer and each atom in the solute molecule.

[0179] The solute-solvent partition function calculation module 400 is used to generate a local partition function for the interaction between water molecules and solute atoms in each solvent layer according to the interaction potential between the three atoms in the water molecules in each solvent layer and each atom in the solute molecule, obtain the partition function for the interaction between water molecules and solute atoms in each solvent layer, and then calculate the total partition function for the interaction of all solute atoms in each solvent layer to obtain the solute-solvent partition function.

[0180] Specifically, the local partition function of the interaction between water molecules and solute atoms in each solvent layer is Calculated by the following formula:

[0181]

[0182] in, is the kth TIP3P water conformation, For TIP3P water molecules The total number of conformations in the solvent layer, i is the solute atom, It is the product of the gas constant and the body temperature.

[0183] The local partition function of the interaction between water molecules and solute atoms in each solvent layer is calculated by the following formula: :

[0184] .

[0185] The local partition function of the interaction between water molecules and solute atoms in each solvent layer is integrated to obtain the total partition function of each solvent layer for the interaction of all solute atoms. ,

[0186]

[0187] Among them, N i is the total number of solute atoms.

[0188] The solvent layer wraps around the solute molecule in 0.1 Å increments, starting from the water accessible surface of the solute molecule and ending at 20 Å from the geometric center of each atom of the solute molecule. The solute-solvent partition function for:

[0189]

[0190] in, The index number of the specific solvent layer, is the number of total solvent layers extending 20 Å from the van der Waals radius of the solute atom to the open space.

[0191] The free energy change calculation module 500 is used to calculate the free energy change caused by the solute-solvent interaction according to the mathematical relationship between the solute-solvent partition function and the free energy.

[0192] The mathematical relationship between the solute-solvent partition function and free energy is:

[0193]

[0194] in, is the solute-solvent free energy.

[0195] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described with reference to the preferred embodiments of the present invention, it should be understood by those skilled in the art that various changes may be made in form and details without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A method for calculating the solvation free energy of a drug molecule, characterized in that: include: The drug molecules and water are simulated as solute molecules and solvent layers, and the continuous solvent layer is evenly distributed outside the solute molecules; The number of water molecules in each solvent layer is calculated by the maximum cross-sectional area of ​​water molecules and the accessible surface area of ​​solvent molecules in each solvent layer; Based on the calculation of the number of water molecules in each solvent layer, the TIP3P model is used to construct a water molecule model in each solvent layer, and the Amber force field is used to calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule, and then the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule is calculated; According to the interaction potential between the three atoms in the water molecules in each solvent layer and each atom in the solute molecule, a local partition function of the interaction between the water molecules in each solvent layer and the solute atoms is generated, and the partition function of the interaction between the water molecules in each solvent layer and the solute atoms is obtained. Then, the total partition function of the interaction between all solute atoms in each solvent layer is calculated to obtain the solute-solvent partition function. The free energy change caused by solute-solvent interaction is calculated based on the mathematical relationship between solute-solvent partition function and free energy; The method of using the Amber force field to calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule, and then calculating the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule includes: The interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule is calculated using the following formula: : Among them, A O-i is the repulsion coefficient between oxygen atom O and solute atom i, A H1-i is the repulsive force coefficient between hydrogen atom H1 and solute atom i, A H2-i is the repulsive force coefficient between another hydrogen atom H2 and solute atom i; B O-i is the attraction coefficient between oxygen atom O and solute atom i, B H1-i is the attraction coefficient between hydrogen atom H1 and solute atom i, B H2-i is the attraction coefficient between another hydrogen atom H2 and solute atom i; r O-i is the distance between oxygen atom O and solute atom i, r H1-i is the distance between hydrogen atom H1 and solute atom i, r H2-i is the distance between hydrogen atom H2 and solute atom i; q O is the charge of the oxygen atom O, q i is the charge of solute atom i, q H1 is the charge of hydrogen atom H1, q H2 is the charge of another hydrogen atom H2; is the interaction potential energy between oxygen atom O and solute atom i, is the interaction potential energy between hydrogen atom H1 and solute atom i, is the interaction potential energy between another hydrogen atom H2 and solute atom i; The interaction potential energy between the three atoms in all water molecules in the solvent layer and each atom in the solute molecule is added together to obtain the interaction potential energy between the three atoms in the water molecules in each solvent layer and each atom in the solute molecule.

2. The method for calculating the solvation free energy of drug molecules according to claim 1, characterized in that: The number of water molecules in each solvent layer Calculated by the following formula: in, is the accessible surface area of ​​solvent molecules in each solvent layer, is the maximum cross-sectional area of ​​a water molecule; the maximum cross-sectional area of ​​a water molecule By calculating the square of the radius of the water molecule multiplied by To obtain, the accessible surface area of ​​solvent molecules in each solvent layer is calculated by the reserved grid space method; The accessible surface area of ​​the solvent molecules in each solvent layer is calculated by retaining the grid space method and includes: For the distance from the center of the solute atom in the solute molecule The solvent layers will have equal spacing And uniformly distributed grid points are placed around each solute atom; The distance from the center of the solute atom Distance in All grid points outside the range are deleted, generating a circle with a distance of , thickness is The grid point sphere shell; The grid points that collide with the entire solute molecular structure are excluded, and the grid points in the spherical shell of the grid points are further deleted; For the remaining grid points, it is used to represent The spatial coordinates of the solvent layer, the The accessible surface area of ​​the solvent molecules of the solvent layer is calculated by the following formula: in, is the number of remaining grid points, is the standard surface area occupied by each grid point.

3. The method for calculating the solvation free energy of drug molecules according to claim 2, characterized in that: The method of constructing a water molecule model in each solvent layer using the TIP3P model based on calculating the number of water molecules in each solvent layer includes: With each atom in the solute molecule as the center, the radius is Construct the solvent layer and place water molecules in each layer using the TIP3P model as geometric parameters. In the solvent layer, the conformation of water molecules is constructed; For each water molecule, a spherical shell grid lattice is generated with the oxygen atom as the center and the oxygen-hydrogen atom bond length as the radius. The spacing between the grid points of the spherical shell grid lattice is 0.1 Å; Place any one of the two hydrogen atoms in the water molecule on each grid point in the spherical shell grid lattice, and based on the geometric positions of oxygen and hydrogen atoms, place the other hydrogen atom on a grid point that satisfies the angle formed by the hydrogen, oxygen and hydrogen atoms of 104.52°; The positions of the two hydrogen atoms were searched and the degenerate state caused by the two equivalent hydrogen atoms in the TIP3P water molecule was excluded to construct the conformations of all TIP3P water molecules in the R-layer solvent layer.

4. The method for calculating the solvation free energy of drug molecules according to claim 3, characterized in that: The local partition function of the interaction between water molecules and solute atoms in each solvent layer is Calculated by the following formula: in, is the kth TIP3P water conformation, For TIP3P water molecules The total number of conformations in the solvent layer, i is the solute atom, is the product of the gas constant and the body temperature; The local partition function of the interaction between water molecules and solute atoms in each solvent layer is calculated by the following formula: : ； The local partition function of the interaction between water molecules and solute atoms in each solvent layer is integrated to obtain the total partition function of each solvent layer for the interaction of all solute atoms. , Among them, N i is the total number of solute atoms; the solvent layer wraps around the solute molecule in increments of 0.1 Å per layer, starting from the water accessible surface of the solute molecule until 20 Å from the geometric center of each atom of the solute molecule. The solute-solvent partition function for: in, The index number of the specific solvent layer, is the number of total solvent layers extending 20Å from the van der Waals radius of the solute atom to the open space.

5. The method for calculating the solvation free energy of drug molecules according to claim 4, characterized in that: The mathematical relationship between the solute-solvent partition function and free energy is: in, is the solute-solvent free energy.

6. A solvation free energy calculation system for drug molecules, characterized in that: It includes simulation module, water molecule number calculation module, interaction potential energy calculation module, solute-solvent partition function calculation module and free energy change calculation module; The simulation module is used to simulate drug molecules and water as solute molecules and solvent layers, and the continuous solvent layer is evenly distributed outside the solute molecules; The water molecule number calculation module is used to calculate the number of water molecules in each solvent layer according to the maximum cross-sectional area of ​​the water molecules and the accessible surface area of ​​the solvent molecules in each solvent layer; The interaction potential energy calculation module is used to calculate the number of water molecules in each solvent layer, construct a water molecule model in each solvent layer using the TIP3P model, calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule using the Amber force field, and then calculate the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule; The solute-solvent partition function calculation module is used to generate a local partition function of the interaction between water molecules and solute atoms in each solvent layer according to the interaction potential between three atoms in the water molecules in each solvent layer and each atom in the solute molecule, obtain the partition function of the interaction between water molecules and solute atoms in each solvent layer, and then calculate the total partition function of each solvent layer for the interaction of all solute atoms to obtain the solute-solvent partition function; The free energy change calculation module is used to calculate the free energy change caused by the solute-solvent interaction according to the mathematical relationship between the solute-solvent partition function and the free energy; The method of using the Amber force field to calculate the interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule, and then calculating the interaction potential energy between the three atoms in the water molecule in each solvent layer and each atom in the solute molecule includes: The interaction potential energy between each atom in the solute molecule and the three atoms in the water molecule is calculated using the following formula: : Among them, A O-i is the repulsion coefficient between oxygen atom O and solute atom i, A H1-i is the repulsive force coefficient between hydrogen atom H1 and solute atom i, A H2-i is the repulsive force coefficient between another hydrogen atom H2 and solute atom i; B O-i is the attraction coefficient between oxygen atom O and solute atom i, B H1-i is the attraction coefficient between hydrogen atom H1 and solute atom i, B H2-i is the attraction coefficient between another hydrogen atom H2 and solute atom i; r O-i is the distance between oxygen atom O and solute atom i, r H1-i is the distance between hydrogen atom H1 and solute atom i, r H2-i is the distance between hydrogen atom H2 and solute atom i; q O is the charge of the oxygen atom O, q i is the charge of solute atom i, q H1 is the charge of hydrogen atom H1, q H2 is the charge of another hydrogen atom H2; is the interaction potential energy between oxygen atom O and solute atom i, is the interaction potential energy between hydrogen atom H1 and solute atom i, is the interaction potential energy between another hydrogen atom H2 and solute atom i; The interaction potential energy between the three atoms in all water molecules in the solvent layer and each atom in the solute molecule is added together to obtain the interaction potential energy between the three atoms in the water molecules in each solvent layer and each atom in the solute molecule.

7. The solvation free energy calculation system of drug molecules according to claim 6, characterized in that: The number of water molecules in each solvent layer Calculated by the following formula: in, is the accessible surface area of ​​solvent molecules in each solvent layer, is the maximum cross-sectional area of ​​a water molecule; the maximum cross-sectional area of ​​a water molecule By calculating the square of the radius of the water molecule multiplied by To obtain, the accessible surface area of ​​solvent molecules in each solvent layer is calculated by the reserved grid space method; The accessible surface area of ​​the solvent molecules in each solvent layer is calculated by retaining the grid space method and includes: For the distance from the center of the solute atom in the solute molecule The solvent layers will have equal spacing And uniformly distributed grid points are placed around each solute atom; The distance from the center of the solute atom Distance in All grid points outside the range are deleted, generating a circle with a distance of , thickness is The grid point sphere shell; The grid points that collide with the entire solute molecular structure are excluded, and the grid points in the spherical shell of the grid points are further deleted; For the remaining grid points, it is used to represent The spatial coordinates of the solvent layer, the The accessible surface area of ​​the solvent molecules of the solvent layer is calculated by the following formula: in, is the number of remaining grid points, is the standard surface area occupied by each grid point.

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