阅读说明：本技术 分子力场拟合方法 (Molecular force field fitting method ) 是由 周云飞 马健 温书豪 赖力鹏 于 2020-04-21 设计创作，主要内容包括：一种分子力场拟合方法,其特征在于,包括：切分：输入大分子3D构象,指定切分位置,将大分子切分为小分子片段,保存小分子片段与输入的大分子之间的原子对应关系；专有力场拟合：对小分子片段进行专有力场拟合,保存拟合好的力场参数；拼接：根据小分子片段与输入的大分子之间的原子对应关系,将拟合后小分子力场拼接成大分子力场；上述分子力场拟合方法将大分子切为较小分子片段,切分原则是在尽可能减少分子自由度(分子复杂度)的同时,保留分子内部临近基团之间的耦合作用,然后分别拟合小分子的力场参数,这个做法弥补了通用力场自身的不足,同时分子量的减少,也相应的减少了量化计算量以及力场参数拟合的难度。(A molecular force field fitting method, comprising: cutting: inputting a macromolecule 3D conformation, designating a segmentation position, segmenting the macromolecule into small molecular fragments, and storing atom corresponding relations between the small molecular fragments and the input macromolecule; fitting of a proprietary force field: carrying out special force field fitting on the small molecular fragments, and storing the fitted force field parameters; splicing: splicing the fitted small molecular force fields into a large molecular force field according to the atom corresponding relation between the small molecular fragments and the input large molecules; according to the molecular force field fitting method, macromolecules are cut into smaller molecular fragments, the principle of cutting is that the degree of freedom (molecular complexity) of molecules is reduced as much as possible, the coupling effect between adjacent groups in the molecules is kept, and then force field parameters of the small molecules are fitted respectively.)

1. A molecular force field fitting method, comprising:

cutting: inputting a macromolecule 3D conformation, designating a segmentation position, segmenting the macromolecule into small molecular fragments, and storing atom corresponding relations between the small molecular fragments and the input macromolecule;

fitting of a proprietary force field: carrying out special force field fitting on the small molecular fragments, and storing the fitted force field parameters;

splicing: and splicing the fitted small molecular force fields into a large molecular force field according to the atom corresponding relation between the small molecular fragments and the input large molecules.

2. The molecular force field fitting method of claim 1, wherein the macromolecular 3D conformation comprises: a unique serial number corresponding to each atom, and a three-dimensional coordinate.

3. The molecular force field fitting method of claim 1, wherein the sites of the cleavage sites are separated by at least three atoms, the groups of the separation part are common groups, the cleaved small molecule fragments comprise common groups, and the cleaved chemical bonds supplement hydrogen atoms at the cleavage sites.

4. The molecular force field fitting method of claim 1, wherein the cleavage preserves coupling between adjacent groups within the macromolecule.

5. The molecular force field fitting method of claim 4, wherein the coupling: and judging whether the positions of the macromolecular adjacent groups have obvious influence on the scanning result when the macromolecular adjacent groups are subjected to flexible dihedral angle scanning.

6. The molecular force field fitting method according to claim 5, characterized in that the flexible dihedral angle scanning is such that the dihedral angle rotates 360 degrees around the middle axis while calculating the energy of each position of the molecule, and the two adjacent groups are judged to have significant influence on each other due to steric hindrance or formation of molecular hydrogen bonds during the dihedral angle scanning, having a coupling effect; when the cleavage is carried out, the site can not be selected between two groups, and the two groups are cleaved into the same molecule.

7. The molecular force field fitting method according to any one of claims 1 to 6, characterized in that the 3D structure of the segmented small molecule fragments and the atomic correspondence between the small molecule fragments and the input macromolecule atoms are returned after segmentation.

8. The molecular force field fitting method of any one of claims 1 to 6, wherein the proprietary force field fitting: and fitting the charge parameters of the small molecular fragments, storing the fitted charge parameter file, fitting bond, angle, dihedral angle and non-bond action item parameters of the small molecular fragments into the parameter file, and calculating the energy of the molecules according to the bond parameters, the angle parameters, the dihedral angle parameters and the non-bond action items.

9. A molecular force field fitting method according to claim 8, wherein the fitting of charge parameters is to calculate the charge carried by each atom, and the non-bonding terms include: electrostatic interactions, van der waals interactions, the bond parameters including: key stretch terms, key angle bend terms, the proprietary force field fitting: calculating the energy of the molecule according to a bond stretching term, a bond angle bending term, an angle parameter, a dihedral angle parameter, an electrostatic action term and a van der Waals action term, wherein the calculation formula is as follows;

wherein k is in key expansion item_bIs the force constant, r is the bond length, r₀Is the length of the key in the equilibrium position;

key angle bending term: k is a radical of_θIs the force constant, theta is the bond angle, theta₀A key angle that is an equilibrium position;

the dihedral angle term Vn represents the highest value of potential energy in the process of dihedral angle rotation, n is used for adjusting periodicity, phi is the value of the variable dihedral angle, and gamma represents the angle of a phase, namely the dihedral angle;

A_ij，B_ij，R_ijis a function of the van der waals parameter,

van der Waals' effects can be expressed by the standard lenard-Jones potential:

in the force field expression: a. the_ij＝4_ijσ_ij ¹²,B_ij＝4_ijσ_ij ⁶

R_ijWhich represents the distance between two atoms, is,_ijrepresenting the depth of the potential well between two atoms, σ_ijIs the distance between two atoms when the potential energy is zero.

Electrostatic interaction expression:

the parameter file includes: atom type definition, molecular topology.

Proprietary force field fitting also includes: and scanning the small molecular fragments to obtain small molecular fragment structures serving as training sets, calculating the energy of the small molecular fragments according to functions, obtaining force field parameters if the correlation between the calculated energy and standard energy is good, and solving various parameter values through iteration.

10. The molecular force field fitting method according to any one of claims 1 to 6, wherein in the splicing step, initial parameters of the input macromolecules are obtained first, and the force field parameters of the input macromolecules are recombined according to the atomic correspondence between the small molecule fragments and the input macromolecules, wherein the initial parameters include molecular topology.

Technical Field

The invention relates to the field of molecular force field analysis, in particular to a molecular force field fitting method.

Background

Molecular force fields can be divided into two broad categories, universal force fields and proprietary force fields, from coverage. Parameters of the universal force field are fitted based on quantitative data of a large number of small molecule fragments or atoms and some experimental data, different types of universal force field are different in definition modes (definition of function forms and atom types), training modes are different, but the general force field has mobility and expansibility and meets certain precision; the special force field is obtained by fitting a specific molecule on the basis of general force field parameters, a training set is used, a certain strategy is adopted to further fit and correct various parameters of the force field, and the description accuracy of the molecule or the molecules is improved accordingly.

In practical application, the universal force field exhibits strong mobility, but has the disadvantage that the universal force field exhibits low precision (the quantitative data is used as a reference, and the correlation with the quantitative data is poor) for some organic molecules with high degrees of freedom, because the parameters of the universal force field are generally the smallest molecular fragments which cover 1-2 flexible angles at most and do not consider the coupling effect between adjacent chemical groups (which can be understood as different dihedral angles) in the actual molecules in order to balance the calculated amount and the universality during fitting, so that the potential energy surface description of the molecules is inaccurate, and the force field possibly causes large structural deviation and energy deviation in simulation.

The existing proprietary force field adopts quantitative data of complete molecules for fitting, so that the defects of a universal force field are overcome, the force field calculation accuracy is improved, but a large amount of quantitative data needs to be prepared in advance to serve as a training set in the proprietary force field. When the degree of freedom of the molecule is higher, the conformation search space is increased, and the calculation amount of quantitative calculation is increased, so that the difficulty and consumption of force field fitting are increased. It is therefore necessary to choose between accuracy and cost.

Disclosure of Invention

Based on this, there is a need to provide a molecular force field fitting method that can balance accuracy and cost.

A molecular force field fitting method, comprising:

cutting: inputting a macromolecule 3D conformation, designating a segmentation position, segmenting the macromolecule into small molecular fragments, and storing atom corresponding relations between the small molecular fragments and the input macromolecule;

fitting of a proprietary force field: carrying out special force field fitting on the small molecular fragments, and storing the fitted force field parameters;

splicing: and splicing the fitted small molecular force fields into a large molecular force field according to the atom corresponding relation between the small molecular fragments and the input large molecules.

In a preferred embodiment, the macromolecular 3D conformation comprises: a unique serial number corresponding to each atom, and a three-dimensional coordinate.

In a preferred embodiment, the cleavage sites are separated by at least three atoms, the groups in the separation part are common groups, the cleaved small molecule fragments comprise common groups, and the cleaved chemical bonds are supplemented with hydrogen atoms at the cleavage sites.

In a preferred embodiment, the cleavage preserves the coupling between adjacent groups within the macromolecule.

In a preferred embodiment, the coupling is: and judging whether the positions of the macromolecular adjacent groups have obvious influence on the scanning result when the macromolecular adjacent groups are subjected to flexible dihedral angle scanning.

In a preferred embodiment, the flexible dihedral angle scanning is that the dihedral angle rotates 360 degrees around the middle shaft, the energy of each position of the molecule is calculated, and when the dihedral angle is scanned, the two adjacent groups judge that the two groups have obvious mutual influence due to steric hindrance effect or molecular hydrogen bond formation, so that the dihedral angle scanning has a coupling effect; when the cleavage is carried out, the site can not be selected between two groups, and the two groups are cleaved into the same molecule.

In a preferred embodiment, the 3D structure of the fragmented small molecule fragments and the atomic correspondence between the small molecule fragments and the input macromolecule atoms are returned after the fragmentation.

In a preferred embodiment, the proprietary force field fits: and fitting the charge parameters of the small molecular fragments, storing the fitted charge parameter file, fitting bond, angle, dihedral angle and non-bond action item parameters of the small molecular fragments into the parameter file, and calculating the energy of the molecules according to the bond parameters, the angle parameters, the dihedral angle parameters and the non-bond action items.

In a preferred embodiment, the fitting of the charge parameters is to calculate the charge carried by each atom, and the non-bonding terms include: electrostatic interactions, van der waals interactions, the proprietary force field fitting: calculating the energy of the molecule according to the bond parameter, the angle parameter, the dihedral angle parameter, the electrostatic interaction term and the van der Waals interaction term; the calculation formula is as follows;

wherein k is in key expansion item_bIs the force constant, r is the bond length, r₀Is the length of the key in the equilibrium position;

key angle bending term: k is a radical of_θIs the force constant, theta is the bond angle, theta₀A key angle that is an equilibrium position;

the dihedral angle term Vn represents the highest value of potential energy in the process of dihedral angle rotation, n is used for adjusting periodicity, phi is the value of the variable dihedral angle, and gamma represents the angle of a phase, namely the dihedral angle;

A_ij，B_ij，R_ijis a function of the van der waals parameter,

van der Waals' effects can be expressed by the standard lenard-Jones potential:in the force field expression: a. the_ij＝4_ijσ_ij ¹²,B_ij＝4_ijσ_ij ⁶

R_ijWhich represents the distance between two atoms, is,_ijrepresenting the depth of the potential well between two atoms, σ_ijIs the distance between two atoms when the potential energy is zero.

Electrostatic interaction expression:

wherein qi and qj are the charges of atoms i and j, respectively, R is the effective dielectric constant_ijIs the distance between two atoms;

the parameter file includes: atom type definition, molecular topology.

Proprietary force field fitting also includes: and scanning the small molecular fragments to obtain small molecular fragment structures serving as training sets, calculating the energy of the small molecular fragments according to functions, obtaining force field parameters if the correlation between the calculated energy and standard energy is good, and solving various parameter values through iteration.

In a preferred embodiment, in the splicing step, initial parameters of the input macromolecules are obtained first, and the force field parameters of the input macromolecules are recombined according to the atomic correspondence between the small molecule fragments and the input macromolecules, wherein the initial parameters include molecular topology.

According to the molecular force field fitting method, macromolecules are cut into smaller molecular fragments, the molecular freedom degree (molecular complexity) is reduced as much as possible, the coupling effect between adjacent groups in molecules is kept, and then force field parameters of small molecules are fitted respectively, so that the defects of a universal force field are overcome. The small molecular fragments are used for constructing a training set to fit a special force field, although the number of molecules is increased, because the degree of freedom of each molecule is low, the search space is greatly reduced when the system conformation search is carried out, the time consumption is reduced, and meanwhile, the difficulty of quantitative calculation and force field parameter fitting is correspondingly reduced due to the reduction of the molecular weight. The method improves the precision of the force field parameters and reduces the difficulty and cost of parameter re-fitting.

Drawings

FIG. 1 is a flow chart of a molecular force field fitting method according to an embodiment of the present invention;

FIG. 2 is a diagram of a macromolecule to be fitted according to one embodiment of the present invention;

FIG. 3 is a 3D plot of the macromolecule to be fitted of FIG. 2;

FIG. 4 is a schematic diagram of the fragmented molecular fragments of the macromolecule to be fitted of FIG. 2.

Detailed Description

As shown in fig. 1, a molecular force field fitting method according to an embodiment of the present invention includes:

step S101, splitting: inputting a macromolecule 3D conformation, designating a segmentation position, segmenting the macromolecule into small molecular fragments, and storing atom corresponding relations between the small molecular fragments and the input macromolecule;

step S103, fitting a proprietary force field: carrying out special force field fitting on the small molecular fragments, and storing the fitted force field parameters;

step S105, splicing: and splicing the fitted small molecular force fields into a large molecular force field according to the atom corresponding relation between the small molecular fragments and the input large molecules.

The 3D conformation of this implementation is not limited in form.

Further, the 3D conformation of the macromolecule of this example includes: a unique serial number corresponding to each atom, and a three-dimensional coordinate.

Further, the cleavage sites of this embodiment are separated by at least three atoms, the groups in the separation part are common groups, the cleaved small molecule fragments include common groups, and the cleaved chemical bonds are supplemented with hydrogen atoms at the cleavage sites.

Further, this example preserves the coupling between adjacent groups within the macromolecule during cleavage.

Further, the coupling effect of the present embodiment: and judging whether the positions of the macromolecular adjacent groups have obvious influence on the scanning result when the macromolecular adjacent groups are subjected to flexible dihedral angle scanning.

Further, the flexible dihedral angle scan of the present embodiment is: the dihedral makes 360 degree rotations around the medial axis while calculating the energy at each position of the molecule.

Furthermore, if two adjacent groups have steric hindrance effect or form molecular hydrogen bond when the dihedral angle is scanned, the mutual influence is judged, and the dihedral angle scanning device has a coupling effect.

Further, the cleavage site in this example cannot be selected between two groups, so that two groups can be cleaved into the same molecule.

Further, the embodiment cuts back the 3D structure of the cut small molecule fragment and the atom correspondence between the small molecule fragment and the input macromolecule atom.

Further, the method of the present embodiment includes a force field fitting step: and fitting the charge parameters of the small molecular fragments, storing the fitted charge parameter file, fitting bond, angle, dihedral angle and non-bond action item parameters of the small molecular fragments into the parameter file, and calculating the energy of the molecules according to the bond parameters, the angle parameters, the dihedral angle parameters and the non-bond action items.

The fitting of the charge parameters to calculate the charge carried by each atom, the non-bonding terms include: electrostatic interactions, van der waals interactions, the bond parameters including: key stretch terms, key angle bend terms, the proprietary force field fitting: calculating the energy of the molecule according to a bond stretching term, a bond angle bending term, an angle parameter, a dihedral angle parameter, an electrostatic action term and a van der Waals action term, wherein the calculation formula is as follows;

wherein k is in key expansion item_bIs the force constant, r is the bond length, r₀Is the length of the key in the equilibrium position;

key angle bending term: k is a radical of_θIs the force constant, theta is the bond angle, theta₀A key angle that is an equilibrium position;

the dihedral angle term Vn represents the highest value of potential energy in the process of dihedral angle rotation, n is used for adjusting periodicity, phi is the value of the variable dihedral angle, and gamma represents the angle of a phase, namely the dihedral angle;

A_ij，B_ij，R_ijis a function of the van der waals parameter,

van der Waals' effects can be expressed by the standard lenard-Jones potential:

in the force field expression: a. the_ij＝4_ijσ_ij ¹²,B_ij＝4_ijσ_ij ⁶

R_ijWhich represents the distance between two atoms, is,_ijrepresenting the depth of the potential well between two atoms, σ_ijIs the distance between two atoms when the potential energy is zero.

Electrostatic interaction expression:wherein qi and qj are the charges of atoms i and j, respectively, R is the effective dielectric constant_ijIs the distance between two atoms.

Wherein: k is a radical of_b，r₀Is a key parameter; k is a radical of_θ，θ₀Is an angle parameter term; vn, γ are dihedral angle parameters; a. the_ij，B_ij，R_ijIs a van der waals parameter; qi, q_jIs an electrostatic parameter.

Further, the parameter file of the embodiment includes: atom type definition, molecular topology.

Proprietary force field fitting also includes: and scanning the small molecular fragments to obtain small molecular fragment structures serving as training sets, calculating the energy of the small molecular fragments according to functions, obtaining force field parameters if the correlation between the calculated energy and standard energy is good, and solving various parameter values through iteration.

Further, the fitting of the charge parameters of the present embodiment is to calculate the charge charged to each atom.

Non-key action items include: electrostatic interactions, van der waals interactions.

Fitting of a proprietary force field: the energy of the molecule is calculated from the bond parameter, the angle parameter, the dihedral angle parameter, the electrostatic interaction term, and the van der waals interaction term.

The parameter file includes: atom type definitions, molecular topology, parameters.

Further, the proprietary force field fitting of the present embodiment: scanning the small molecular fragments to obtain small molecular fragment structures as training sets, calculating the energy of the small molecular fragments according to a formula (1), obtaining force field parameters if the correlation between the calculated energy and standard energy is good, and solving various parameter values through iteration.

As shown in fig. 2 to 4, in one embodiment of the present invention, the 3D structure (shown in fig. 3) of the macromolecule to be fitted (shown in fig. 2) corresponds to a unique serial number and three-dimensional coordinates for each atom.

Cutting: the sites to be cut, namely the chemical bonds to be cut, are selected according to requirements, the sites must be separated by at least three atoms, the groups are separated to be called shared groups, the cut fragments all contain the shared groups (the purpose is to ensure the dihedral angle parameter integrity of the original molecular force field), and the cut chemical bonds automatically supplement hydrogen atoms at the cut positions to ensure the chemical integrity of the small molecules. If the molecules are split into three small molecules of Mol1, Mol2 and Mol3 (shown in figure 4), the split sites are bond:19-20,22-28,28-29 and 32-39 (shown in figure 3). Defining the site of the cleavage: slicing _ groups [ ((22,28), (19,20)), ((19,20), (32,39)), ((28,29), (32,39)) ], and the procedure returns the 3D structure (mol1, mol2, mol3) of the three small molecules after being fragmented (as shown in fig. 4), and the correspondence between the small molecule fragments and the atoms of the original molecule (the input macromolecule to be fitted).

Fitting of a proprietary force field: and fitting the charge parameters of the input macromolecules to be fitted, storing a charge parameter file after fitting, fitting bonds, angles, dihedral angles and van der Waals parameters of the three micromolecule fragments, and storing the parameter files (such as mol1_ ff, mol2_ ff and mol3_ ff). The initial parameters may be the parameters of the Gaff2 force field which can be obtained free of charge.

Splicing: firstly, an initial parameter file (such as Model _ ff, including the molecular topology) of the Model _ molecule (macromolecule to be fitted) is obtained by using Gaff2, and then the force field parameters of the original molecule (macromolecule to be fitted) are recombined by using the atomic correspondence between the small molecule fragments and the original molecule (macromolecule to be fitted). Wherein, the bond, angle, dihedral angle and Van der Waals parameters are combined by the force field parameters of each small molecular fragment according to the corresponding relation, and the charge parameters are parameters which are independently fitted by the original molecules (macromolecules to be fitted) so as to ensure the rationality of charge distribution.

Proprietary force field fitting requires: 1. the objective function is a function form to be solved, as shown in formula (1); 2. a training set, a molecular structure with QM energy, wherein the cut small molecular fragments are scanned to obtain a batch of structures as the training set (the reference term of the force field, namely the energy calculated by the fitted function has good correlation with the standard QM, and good force field parameters are obtained); 3. and the algorithm is used for solving the function, and various parameter values are solved through continuous iteration by adopting a quasi-Newton method BFGS algorithm. The method for fitting the molecular force field parameters of each fragment is the same method. The initial parametric forms are the same and can be chosen from Gaff2, and charge fitting is the calculation of the charge carried by each atom.

The molecular force field fitting method of the invention comprises the following steps of automatically cutting molecules: the algorithm can segment the macromolecules according to the manually specified segmentation sites, and automatically replenishes hydrogen atoms at the positions of broken bonds so as to ensure the integrity of the molecules and simultaneously store the atom mapping relationship between fragment molecules and the macromolecules.

Splicing small molecule fragment force field parameters: the automatic splicing tool can reconstruct the force field parameter file of the main body molecule according to the corresponding relationship of atoms stored during segmentation of the force field parameters after the refitting of the small molecule fragments.

The invention utilizes the principle of cutting macromolecules into smaller molecular fragments, retains the coupling effect between adjacent groups in molecules while reducing the degree of freedom (molecular complexity) of the molecules as much as possible, and then respectively fits the force field parameters of the small molecules, thereby making up the defects of the general force field. The small molecular fragments are used for constructing a training set to fit a special force field, although the number of molecules is increased, because the degree of freedom of each molecule is low, the search space is greatly reduced when the system conformation search is carried out, the time consumption is reduced, and meanwhile, the difficulty of quantitative calculation and force field parameter fitting is correspondingly reduced due to the reduction of the molecular weight. The method improves the precision of the force field parameters and reduces the difficulty and cost of parameter re-fitting.

The molecular force field fitting method is tested on a plurality of systems, and through comparison, the precision of the fitted force field is higher than the initial general force field parameter (gaff) and is equivalent to the precision of a conventional fitted proprietary force field, but the calculation amount is obviously less than the consumption of macromolecules in the same fitting process.

The molecular force field fitting method is different from the practical parameterization process of a general force field, takes the interaction among groups in molecules into consideration, and is more accurate in description of the potential energy surface of the molecules and higher in precision. According to the splicing method of the force field parameters, the force field splicing tool can automatically splice the parameters after fitting of the small molecular fragments into a complete large molecular force field parameter file by utilizing the mapping relation reserved in cutting, so that the method has a good auxiliary function, and manual operation is reduced.

In light of the foregoing description of the preferred embodiments according to the present application, it is to be understood that various changes and modifications may be made without departing from the spirit and scope of the invention. The technical scope of the present application is not limited to the contents of the specification, and must be determined according to the scope of the claims.

As will be appreciated by one skilled in the art, embodiments of the present application may be provided as a method, system, or computer program product. Accordingly, the present application may take the form of an entirely hardware embodiment, an entirely software embodiment or an embodiment combining software and hardware aspects. Furthermore, the present application may take the form of a computer program product embodied on one or more computer-usable storage media (including, but not limited to, disk storage, CD-ROM, optical storage, and the like) having computer-usable program code embodied therein.

The present application is described with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the application. It will be understood that each flow and/or block of the flow diagrams and/or block diagrams, and combinations of flows and/or blocks in the flow diagrams and/or block diagrams, can be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general purpose computer, special purpose computer, embedded processor, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions specified in the flowchart flow or flows and/or block diagram block or blocks.

These computer program instructions may also be stored in a computer-readable memory that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instruction means which implement the function specified in the flowchart flow or flows and/or block diagram block or blocks.

These computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide steps for implementing the functions specified in the flowchart flow or flows and/or block diagram block or blocks.