Method and device for generating initial structure of small molecule transition state based on conformation and force field

Abstract

A method and device for generating the initial structure of a small molecule transition state based on conformation and force field, the method generates the initial conformation of the input molecule and optimizes the structure according to the bond connection relationship of the atoms in the input molecule through the molecular structure generation strategy; the input molecule is rotated and translated to determine the relative orientation to complete the initialization of the splicing structure; the rotational inertia and total mass of the input molecule are calculated; the interaction forces between the atoms of several input molecules and the interaction forces between the splicing sites are calculated; the force on each atom in the input molecule is decomposed into the force and torque passing through the center of mass of the input molecule; the translational displacement and rotational displacement of the input molecule are calculated, and the coordinates of the atoms in the input molecule are updated; the final structure after the splicing of several input molecules is output through iterative calculation and update. The present invention can effectively avoid the problem of atomic overlap during the splicing process and ensure that the selected splicing sites are kept at the shortest distance.

Description

Technical Field

[0001] The present invention relates to the technical field of small molecule structure generation, and in particular to a method and device for generating a small molecule transition state initial structure based on conformation and force field. Background Art

[0002] When searching for molecular transition states, the initial conformation of the structure must first be determined. Currently, the most commonly used method is to manually position the molecules, but manual operation is obviously not feasible in high-throughput computing scenarios.

[0003] Current conformation generation algorithms are generally aimed at single-molecule conformation generation. When generating multi-molecule conformations, there are problems such as atomic overlap, bond overlap, or reaction sites that are too far apart or molecular orientation errors. This problem has become a bottleneck in the search for small molecule transition states. Although the existing transition state search algorithms are relatively mature, how to reasonably splice the initial conformations of small molecules in high-throughput calculations is still a challenge.

[0004] Therefore, how to design a method for generating the initial structure of the small molecule transition state that can effectively avoid the problem of atomic overlap and ensure that the selected splicing sites are kept at the shortest distance has become an urgent problem to be solved. Summary of the invention

[0005] To this end, the present invention provides a method and device for generating the initial structure of a small molecule transition state based on conformation and force field, which can effectively avoid the problem of atomic overlap during the splicing process and ensure that the selected splicing sites are kept at the shortest distance. In addition, the method can also ensure that the geometric structure of the molecule does not change during the splicing process, thereby improving the accuracy and efficiency of the transition state search.

[0006] In order to achieve the above object, the present invention provides the following technical solution: a method for generating the initial structure of a small molecule transition state based on conformation and force field, comprising:

[0007] Determine the bond connection relationship of atoms in the input molecule through the input SMILES; generate an initial conformation of the input molecule through a molecular structure generation strategy based on the bond connection relationship of atoms in the input molecule; perform structural optimization on the initial conformation of the input molecule through an energy-based optimization algorithm;

[0008] According to the charge information of atoms in the input molecules or the charge information of the electrostatic potential on the surface of the input molecules, the positions where the input molecules attract each other are determined; according to the positions where the input molecules attract each other, the input molecules are rotated and translated to determine the relative orientation of the input molecules, thereby completing the initialization of the splicing structure of the input molecules;

[0009] By setting the calculation strategy, the moment of inertia and total mass of the input molecule are calculated;

[0010] According to the interaction potential between atoms and the interaction potential between splicing sites, the interaction forces between atoms of a number of input molecules and the interaction forces between splicing sites of a number of input molecules are calculated;

[0011] Decomposing the interaction force between atoms on each atom in the input molecule into a force and a torque passing through the center of mass of the input molecule; calculating the translational displacement and the rotational displacement of the input molecule according to the force and the torque passing through the center of mass of the input molecule; updating the coordinates of the atoms in the input molecule according to the translational displacement and the rotational displacement of the input molecule;

[0012] According to the coordinates of the atoms in the updated input molecules, iterative calculation updates are performed until the calculation upper limit is reached or the distance between the splicing sites of several input molecules meets the set value, the iterative calculation updates are stopped, and the final structure after splicing of several input molecules is output.

[0013] As a preferred scheme for the method of generating the initial structure of the small molecule transition state based on conformation and force field, in the process of generating the initial conformation of the input molecule according to the bond connection relationship of atoms in the input molecule through the molecular structure generation strategy, the molecular structure generation strategy includes systematic search, model construction, random search, distance geometry, molecular dynamics, and Monte Carlo strategy.

[0014] As a preferred embodiment of the method for generating the initial structure of the transition state of a small molecule based on conformation and force field, in the process of optimizing the structure of the initial conformation of the input molecule by the energy-based optimization algorithm, the energy-based optimization algorithm includes a molecular energy calculation strategy and an optimization algorithm;

[0015] The molecular energy calculation strategies include: molecular force field strategy and semi-empirical strategy; wherein the semi-empirical strategy includes DFTB, xTB, PM6, PM7;

[0016] The optimization algorithms include: conjugate gradient method, Newton method and steepest descent method.

[0017] As a preferred solution of the method for generating the initial structure of the transition state of a small molecule based on conformation and force field, in the process of calculating the moment of inertia and the total mass of the input molecule by setting the calculation strategy, when calculating the moment of inertia, the mass of the atom is set to the relative atomic mass; the calculation formula of the moment of inertia is:

[0018]

[0019] Where I is the calculated moment of inertia, i is the number of the atom, and m is i is the relative atomic mass of the ith atom; R iis the distance of the ith atom from the rotation axis, where the rotation axis is defined as the vector pointing in the direction of the torque through the center of mass of the molecule.

[0020] As a preferred solution of the method for generating the initial structure of the transition state of a small molecule based on conformation and force field, the calculation formula of the interaction force between the atoms of several input molecules is:

[0021]

[0022] In the formula, is the interaction potential between the i-th and j-th atoms, r ij is the distance between the i-th and j-th atoms.

[0023] As a preferred solution of the method for generating the initial structure of the transition state of a small molecule based on conformation and force field, in the process of calculating the translational displacement and the rotational displacement of the input molecule according to the force and torque passing through the center of mass of the input molecule, the calculation formula of the translational displacement is:

[0024]

[0025] In the formula, F 1 is the force passing through the molecular mass center; M is the mass of the molecule; x is the translational displacement;

[0026] The calculation formula of the rotation displacement is:

[0027]

[0028] Where θ is the rotational displacement; τ is the torque; and I is the moment of inertia.

[0029] As a preferred solution of the method for generating the initial structure of the transition state of a small molecule based on conformation and force field, when the distance between the splicing sites of several input molecules meets the set value, the iterative calculation and updating process is stopped, and the calculation formula of the distance between the splicing sites is:

[0030]

[0031] Where d is the distance between splicing sites; x 1 and x 2 Represents the geometric coordinates of splice site 1 and splice site 2.

[0032] The present invention also provides a device for generating an initial structure of a small molecule transition state based on conformation and force field, based on the above method for generating an initial structure of a small molecule transition state based on conformation and force field, comprising:

[0033] The initial conformation generation and optimization module is used to determine the bond connection relationship of atoms in the input molecule through the input SMILES; generate the initial conformation of the input molecule through the molecular structure generation strategy according to the bond connection relationship of atoms in the input molecule; and perform structural optimization on the initial conformation of the input molecule through the energy-based optimization algorithm;

[0034] The molecular splicing structure initialization module is used to determine the positions of mutual attraction between input molecules according to the charge information of atoms in the input molecules or the charge information of the electrostatic potential on the surface of the input molecules; according to the positions of mutual attraction between the input molecules, the input molecules are rotated and translated to determine the relative orientation of the input molecules, thereby completing the initialization of the input molecular splicing structure;

[0035] The molecular moment of inertia and total mass calculation module is used to calculate the moment of inertia and total mass of the input molecule by setting the calculation strategy;

[0036] An interaction force calculation module, used for calculating the interaction forces between atoms of a plurality of input molecules and the interaction forces between splicing sites of a plurality of input molecules according to the interaction potential between atoms and the interaction potential between splicing sites;

[0037] an atomic coordinate updating module, for decomposing the interaction force between atoms on each atom in the input molecule into a force and a torque passing through the center of mass of the input molecule; calculating the translational displacement and the rotational displacement of the input molecule according to the force and the torque passing through the center of mass of the input molecule; and updating the coordinates of the atoms in the input molecule according to the translational displacement and the rotational displacement of the input molecule;

[0038] The final structure output module is used to perform iterative calculation updates based on the coordinates of atoms in the updated input molecules until the calculation upper limit is reached or the distance between the splicing sites of several input molecules meets the set value, stop the iterative calculation update, and output the final structure after splicing several input molecules.

[0039] As a preferred solution of the device for generating the initial structure of the transition state of a small molecule based on conformation and force field, in the initial conformation generation and optimization module, in the process of generating the initial conformation of the input molecule according to the bond connection relationship of atoms in the input molecule through the molecular structure generation strategy, the molecular structure generation strategy includes systematic search, model construction, random search, distance geometry, molecular dynamics, and Monte Carlo strategy.

[0040] As a preferred solution of the device for generating the initial structure of the transition state of a small molecule based on conformation and force field, in the initial conformation generation and optimization module, in the process of optimizing the structure of the initial conformation of the input molecule by the energy-based optimization algorithm, the energy-based optimization algorithm includes a molecular energy calculation strategy and an optimization algorithm;

[0041] The molecular energy calculation strategies include: molecular force field strategy and semi-empirical strategy; wherein the semi-empirical strategy includes DFTB, xTB, PM6, PM7;

[0042] The optimization algorithms include: conjugate gradient method, Newton method and steepest descent method.

[0043] As a preferred solution of the device for generating the initial structure of the transition state of a small molecule based on conformation and force field, in the molecular moment of inertia and total mass calculation module, in the process of calculating the moment of inertia and the total mass of the input molecule by setting the calculation strategy, when calculating the moment of inertia, the mass of the atom is set to the relative atomic mass; the calculation formula of the moment of inertia is:

[0044]

[0045] Where I is the calculated moment of inertia, i is the number of the atom, and m is i is the relative atomic mass of the ith atom; R i is the distance of the ith atom from the rotation axis, where the rotation axis is defined as the vector pointing in the direction of the torque through the center of mass of the molecule.

[0046] As a preferred solution of the device for generating the initial structure of the transition state of a small molecule based on conformation and force field, in the interaction force calculation module, the calculation formula of the interaction force between the atoms of several input molecules is:

[0047]

[0048] In the formula, is the interaction potential between the i-th and j-th atoms, r ij is the distance between the i-th and j-th atoms.

[0049] As a preferred solution of the device for generating the initial structure of the transition state of a small molecule based on conformation and force field, in the atomic coordinate updating module, in the process of calculating the translational displacement and the rotational displacement of the input molecule according to the force and torque passing through the center of mass of the input molecule, the calculation formula of the translational displacement is:

[0050]

[0051] In the formula, F 1 is the force passing through the molecular mass center; M is the mass of the molecule; x is the translational displacement;

[0052] The calculation formula of the rotation displacement is:

[0053]

[0054] Where θ is the rotational displacement; τ is the torque; and I is the moment of inertia.

[0055] As a preferred solution of the device for generating the initial structure of the transition state of a small molecule based on conformation and force field, in the final structure output module, when the distance between the splicing sites of several input molecules meets the set value, the iterative calculation and updating process is stopped, and the calculation formula of the distance between the splicing sites is:

[0056]

[0057] Where d is the distance between splicing sites; x 1 and x 2 Represents the geometric coordinates of splice site 1 and splice site 2.

[0058] The present invention has the following advantages: determining the bond connection relationship of atoms in an input molecule by inputting SMILES; generating an initial conformation of the input molecule by molecular structure generation strategy according to the bond connection relationship of atoms in the input molecule; optimizing the structure of the initial conformation of the input molecule by energy-based optimization algorithm; determining the position of mutual attraction between the input molecules according to the charge information of atoms in the input molecule or the charge information of the surface electrostatic potential of the input molecule; rotating and translating the input molecule according to the position of mutual attraction between the input molecules to determine the relative orientation of the input molecule and complete the initialization of the splicing structure of the input molecule; calculating and obtaining the rotational inertia and total mass of the input molecule by setting the calculation strategy; optimizing the structure of the initial conformation of the input molecule by energy-based optimization algorithm; determining the position of mutual attraction between the input molecules according to the charge information of atoms in the input molecule or the charge information of the surface electrostatic potential of the input molecule; performing rotation and translation on the input molecule according to the position of mutual attraction between the input molecules to determine the relative orientation of the input molecule and complete the initialization of the splicing structure of the input molecule; calculating and obtaining the rotational inertia and total mass of the input molecule by setting the calculation strategy; optimizing the structure of the initial conformation of the input molecule according to the interaction potential between atoms and the splicing potential; optimizing the structure of the initial conformation of the input molecule by energy-based optimization algorithm ... The interaction potential between the joint sites is used to calculate the interaction force between the atoms of several input molecules and the interaction force between the splicing sites of several input molecules; the interaction force between the atoms received by each atom in the input molecule is decomposed into the force and torque passing through the center of mass of the input molecule; according to the force and torque passing through the center of mass of the input molecule, the translational displacement and rotational displacement of the input molecule are calculated; the coordinates of the atoms in the input molecule are updated according to the translational displacement and the rotational displacement of the input molecule; according to the coordinates of the atoms in the updated input molecule, iterative calculation and update are performed until the calculation upper limit is reached or the distance between the splicing sites of several input molecules meets the set value, the iterative calculation and update are stopped, and the final structure after the splicing of several input molecules is output. The present invention generates a reasonable initial conformation for transition state search by combining small molecule conformation generation technology and small molecule rigid docking technology based on force field. The present invention can effectively avoid the problem of atomic overlap during the splicing process and ensure that the selected splicing site is kept at the shortest distance. In addition, the method can also ensure that the geometric structure of the molecule does not change during the splicing process, thereby improving the accuracy and efficiency of the transition state search. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] In order to more clearly illustrate the implementation methods of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for the implementation methods or the description of the prior art. Obviously, the drawings in the following description are only exemplary, and for ordinary technicians in this field, other implementation drawings can be derived from the provided drawings without creative work.

[0060] The structures, proportions, sizes, etc. illustrated in this specification are only used to match the contents disclosed in the specification so as to facilitate understanding and reading by persons familiar with the technology. They are not used to limit the conditions under which the present invention can be implemented, and therefore have no substantial technical significance. Any structural modification, change in proportion or adjustment of size shall still fall within the scope of the technical contents disclosed in the present invention without affecting the effects and purposes that can be achieved by the present invention.

[0061] Figure 1 This is a schematic diagram of the process of generating the initial structure of a small molecule transition state based on conformation and force field provided in Example 1 of the present invention;

[0062] Figure 2 A schematic diagram of the initial structure of the docking of vinyl alcohol and formaldehyde in a possible embodiment provided in Example 1 of the present invention; wherein green represents C atoms, red represents O atoms, white represents H atoms, and blue represents splicing sites;

[0063] Figure 3 A schematic diagram of the final structure of the splicing of vinyl alcohol-formaldehyde molecules in a possible embodiment provided in Example 1 of the present invention; wherein green represents C atoms, red represents O atoms, white represents H atoms, and blue represents splicing sites;

[0064] Figure 4 Schematic diagram of the architecture of the device for generating the initial structure of the small molecule transition state based on conformation and force field provided in Example 2 of the present invention. DETAILED DESCRIPTION

[0065] The following is a description of the implementation of the present invention by specific embodiments. People familiar with the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0066] Example 1

[0067] See also Figure 1 Embodiment 1 of the present invention provides a method for predicting medium- and long-term paths of a multivariable regional energy structure, comprising the following steps:

[0068] S1. Determine the bond connection relationship of atoms in the input molecule through the input SMILES; generate an initial conformation of the input molecule through a molecular structure generation strategy according to the bond connection relationship of atoms in the input molecule; perform structural optimization on the initial conformation of the input molecule through an energy-based optimization algorithm;

[0069] S2. Determine the positions where the input molecules attract each other based on the charge information of atoms in the input molecules or the charge information of the electrostatic potential on the surface of the input molecules; rotate and translate the input molecules based on the positions where the input molecules attract each other, determine the relative orientation of the input molecules, and complete the initialization of the splicing structure of the input molecules;

[0070] S3, calculating and obtaining the moment of inertia and total mass of the input molecule by setting the calculation strategy;

[0071] S4. According to the interaction potential between atoms and the interaction potential between splicing sites, the interaction forces between atoms of a plurality of input molecules and the interaction forces between splicing sites of a plurality of input molecules are calculated;

[0072] S5, decomposing the interaction force between atoms on each atom in the input molecule into a force and a torque passing through the center of mass of the input molecule; calculating the translational displacement and the rotational displacement of the input molecule according to the force and the torque passing through the center of mass of the input molecule; updating the coordinates of the atoms in the input molecule according to the translational displacement and the rotational displacement of the input molecule;

[0073] S6. Perform iterative calculation and update according to the coordinates of the atoms in the updated input molecules until the calculation upper limit is reached or the distance between the splicing sites of several input molecules meets the set value, stop the iterative calculation and update, and output the final structure after splicing several input molecules.

[0074] In this embodiment, in step S1, the bond connection relationship of atoms in the input molecule is determined by the input SMILES; according to the bond connection relationship of atoms in the input molecule, an initial conformation of the input molecule is generated by a molecular structure generation strategy; and the initial conformation of the input molecule is structurally optimized by an energy-based optimization algorithm;

[0075] Specifically, in the process of generating the initial conformation of the input molecule according to the bond connection relationship of atoms in the input molecule through the molecular structure generation strategy, the molecular structure generation strategy includes but is not limited to search, model building, random search, distance geometry, molecular dynamics, Monte Carlo method and other conformation generation algorithms based on the atomic bond relationship, atomic interaction and atomic distance in the molecule.

[0076] In the process of structurally optimizing the initial conformation of the input molecule by the energy-based optimization algorithm, the energy-based optimization algorithm includes a molecular energy calculation strategy and an optimization algorithm;

[0077] The molecular energy calculation strategies include: molecular force field strategy and semi-empirical strategy; wherein the semi-empirical strategy includes but is not limited to DFTB, xTB, PM6, PM7 and other strategies for approximate rapid calculation of molecular energy;

[0078] The optimization algorithms include but are not limited to the conjugate gradient method, Newton's method, steepest descent method and other optimization algorithms based on the first-order gradient and second-order gradient of energy.

[0079] In this embodiment, in step S2, the positions where the input molecules attract each other are determined according to the charge information of the atoms in the input molecules or the charge information of the electrostatic potential on the surface of the input molecules; according to the positions where the input molecules attract each other, the input molecules are rotated and translated to determine the relative orientation of the input molecules, thereby completing the initialization of the splicing structure of the input molecules;

[0080] Specifically, the initial structure of the input molecule is adjusted according to the position of the splicing site relative to the input molecule. The four points of the centroids and the splicing site of the two molecules are on the same straight line, and the vector with the splicing site of the first molecule as the end point and the centroid of the first molecule as the starting point is opposite to the vector with the splicing site of the second molecule as the end point and the centroid of the second molecule as the starting point.

[0081] In this embodiment, in step S3, the moment of inertia and total mass of the input molecule are calculated by setting a calculation strategy;

[0082] Specifically, when calculating the moment of inertia, the mass of the atom is set as the relative atomic mass; the splicing site is regarded as a pseudoatom, and the relative atomic mass of the pseudoatom is 0.

[0083] The calculation formula of the moment of inertia is:

[0084]

[0085] Where I is the calculated moment of inertia, i is the number of the atom, and m is i is the relative atomic mass of the ith atom; R i is the distance of the ith atom from the rotation axis, where the rotation axis is defined as the vector pointing in the direction of the torque through the center of mass of the molecule.

[0086] In this embodiment, in step S4, the interaction forces between atoms of a plurality of input molecules and the interaction forces between splicing sites of a plurality of input molecules are calculated based on the interaction potential between atoms and the interaction potential between splicing sites;

[0087] Specifically, the interaction forces between atoms belonging to different molecules and the interaction forces between splicing sites are calculated. The interactions between atoms belonging to the same molecule are not calculated, and the interactions between splicing sites and atoms are not considered. The interaction potential between atoms includes weak interaction potential and electrostatic interaction potential. Among them, the electrostatic interaction potential and the weak interaction potential include but are not limited to Lennard-Jones and its variants, oscillator potential, hard sphere potential, etc. The interaction between atoms is a repulsive potential when the distance is greater than the van der Waals radius. The interaction potential between splicing sites is a constant attraction potential, and the forms of the interaction potential include but are not limited to the oscillator potential, Lennard-Jones potential, etc.

[0088] The calculation formula for the interaction force between atoms of several input molecules is:

[0089]

[0090] In the formula, is the interaction potential between the i-th and j-th atoms, r ij is the distance between the i-th and j-th atoms.

[0091] In this embodiment, in step S5, the interaction force between atoms on each atom in the input molecule is decomposed into a force and a torque passing through the center of mass of the input molecule; the translational displacement and the rotational displacement of the input molecule are calculated based on the force and the torque passing through the center of mass of the input molecule; the coordinates of the atoms in the input molecule are updated based on the translational displacement and the rotational displacement of the input molecule;

[0092] Specifically, the force on each atom is decomposed into perpendicular translational force and rotational force, and the torque generated by the force on the molecule as a whole is calculated based on the rotational force, the coordinates of the atom, and the coordinates of the center of mass. All translational forces and rotational moments are added together, and the translational displacement and rotational displacement of the molecule are calculated based on the calculated total translational force and total moment. The coordinates of the atom are updated based on the calculated translational displacement and rotational displacement.

[0093] Wherein, the calculation formula of the translational displacement is:

[0094]

[0095] In the formula, F 1 is the force passing through the molecular mass center; M is the mass of the molecule; x is the translational displacement;

[0096] The calculation formula of the rotation displacement is:

[0097]

[0098] Where θ is the rotational displacement; τ is the torque; and I is the moment of inertia.

[0099] In this embodiment, in step S6, iterative calculation and updating are performed according to the coordinates of the atoms in the updated input molecules until the calculation upper limit is reached or the distance between the splicing sites of several input molecules meets the set value, the iterative calculation and updating are stopped, and the final structure after splicing of several input molecules is output.

[0100] Specifically, according to the coordinates of the atoms in the updated input molecules, steps S4 and S5 are iterated until the calculation upper limit is reached or the distance between the splicing sites of several input molecules meets the set value, the iterative calculation update is stopped, and the geometric coordinates of the atoms in the spliced ​​molecules are output. The molecular structure at this time is the final structure after the molecules are spliced ​​together.

[0101] The distance between splicing sites is calculated as:

[0102]

[0103] Where d is the distance between splicing sites; x 1 and x 2 Represents the geometric coordinates of splice site 1 and splice site 2.

[0104] In a possible embodiment, an electrostatic potential extreme point in the vinyl alcohol-formaldehyde molecule is provided as a splicing site, and an example of generating the initial structure of the small molecule transition state is as follows:

[0105] T1. Generate 3D conformations of vinyl alcohol and formaldehyde. The SMILES of vinyl alcohol and formaldehyde are C=CO and CO respectively. Use the configuration generation tool in the RDkit tool to generate the initial 3D conformations of the two molecules. Single molecule structure optimization, using xtb at the gfn2 level for structure optimization.

[0106] T2, then use Python to rotate and translate the molecular structure so that the orientation of the splicing sites is relative; Figure 2 As shown;

[0107] T3. Calculate the moment of inertia and total mass of the two molecules;

[0108] T4. Only the van der Waals interaction between atoms is considered, and the interaction is calculated using the parameters of the UFF force field and the Lennard-Jones potential; the interaction between the splicing sites is set to the harmonic oscillator potential, and the force constant is set to 1; the radius of the molecule is calculated using the van der Waals interaction parameters of the UFF force field, and the force field parameters used are shown in Table 1;

[0109]

[0110] Table 1 Calculation of force field parameters of molecular forces The calculation formula for energy uses the Lennard-Jones potential:

[0111]

[0112] In the formula, x represents the distance between atoms, and σ and ε represent the Lennard-Jones force field parameters.

[0113] The interaction force between molecules only calculates the interaction force between atoms belonging to different molecules. The splicing site has no interaction force on the atom. The interaction potential between the splicing sites is selected as the oscillator potential. The function form is as follows

[0114] E=ax 2

[0115] Where x represents the distance of the splicing site and a represents the interaction strength.

[0116] T5. Take T3 and T4 as the first iteration cycle to calculate the total translational force and total torque on the vinyl alcohol molecule. Translate the vinyl alcohol molecule and the formaldehyde molecule according to the force;

[0117] T6, continuous iteration, the final iteration number is 13 steps, the structure after splicing is as follows Figure 3 shown.

[0118] In summary, the present invention determines the bond connection relationship of atoms in the input molecule through the input SMILES; generates the initial conformation of the input molecule through the molecular structure generation strategy according to the bond connection relationship of atoms in the input molecule; performs structural optimization on the initial conformation of the input molecule through the energy-based optimization algorithm; determines the position of mutual attraction between the input molecules according to the charge information of atoms in the input molecule or the charge information of the surface electrostatic potential of the input molecule; rotates and translates the input molecule according to the position of mutual attraction between the input molecules, determines the relative orientation of the input molecule, and completes the initialization of the splicing structure of the input molecule; calculates the moment of inertia and total mass of the input molecule by setting the calculation strategy; and optimizes the structure of the initial conformation of the input molecule according to the interaction potential between atoms and the splicing potential. The interaction potential between the sites is used to calculate the interaction forces between the atoms of several input molecules and the interaction forces between the splicing sites of several input molecules; the interaction forces between the atoms received by each atom in the input molecule are decomposed into forces and torques passing through the center of mass of the input molecule; according to the forces and torques passing through the center of mass of the input molecule, the translational displacement and rotational displacement of the input molecule are calculated; the coordinates of the atoms in the input molecule are updated according to the translational displacement and the rotational displacement of the input molecule; according to the coordinates of the atoms in the updated input molecule, iterative calculation updates are performed until the calculation upper limit is reached or the distance between the splicing sites of several input molecules meets the set value, the iterative calculation update is stopped, and the final structure after the splicing of several input molecules is output. The present invention generates a reasonable initial conformation for transition state search by combining small molecule conformation generation technology and small molecule rigid docking technology based on force field. The present invention can effectively avoid the problem of atomic overlap during the splicing process and ensure that the selected splicing site is kept at the shortest distance. In addition, the method can also ensure that the geometric structure of the molecule does not change during the splicing process, thereby improving the accuracy and efficiency of the transition state search.

[0119] It should be noted that the method of the embodiment of the present disclosure can be performed by a single device, such as a computer or a server. The method of the present embodiment can also be applied in a distributed scenario and completed by multiple devices cooperating with each other. In the case of such a distributed scenario, one of the multiple devices can only perform one or more steps in the method of the embodiment of the present disclosure, and the multiple devices will interact with each other to complete the described method.

[0120] It should be noted that the above describes some embodiments of the present disclosure. Other embodiments are within the scope of the appended claims. In some cases, the actions or steps recorded in the claims can be performed in an order different from that in the above embodiments and still achieve the desired results. In addition, the processes depicted in the accompanying drawings do not necessarily require the specific order or continuous order shown to achieve the desired results. In some embodiments, multitasking and parallel processing are also possible or may be advantageous.

[0121] Example 2

[0122] See also Figure 4 Embodiment 2 of the present invention also provides a small molecule transition state initial structure generation device based on conformation and force field, comprising:

[0123] The initial conformation generation and optimization module 001 is used to determine the bond connection relationship of atoms in the input molecule through the input SMILES; generate the initial conformation of the input molecule through the molecular structure generation strategy according to the bond connection relationship of atoms in the input molecule; and perform structural optimization on the initial conformation of the input molecule through the energy-based optimization algorithm;

[0124] The molecular splicing structure initialization module 002 is used to determine the positions of mutual attraction between the input molecules according to the charge information of the atoms in the input molecules or the charge information of the electrostatic potential on the surface of the input molecules; according to the positions of mutual attraction between the input molecules, the input molecules are rotated and translated to determine the relative orientation of the input molecules, and the initialization of the input molecular splicing structure is completed;

[0125] The molecular moment of inertia and total mass calculation module 003 is used to calculate the moment of inertia and total mass of the input molecule by setting a calculation strategy;

[0126] An interaction force calculation module 004 is used to calculate the interaction forces between atoms of a plurality of input molecules and the interaction forces between splicing sites of a plurality of input molecules according to the interaction potential between atoms and the interaction potential between splicing sites;

[0127] The atomic coordinate updating module 005 is used to decompose the interaction force between atoms on each atom in the input molecule into a force and a torque passing through the center of mass of the input molecule; calculate the translational displacement and the rotational displacement of the input molecule according to the force and the torque passing through the center of mass of the input molecule; and update the coordinates of the atoms in the input molecule according to the translational displacement and the rotational displacement of the input molecule;

[0128] The final structure output module 006 is used to perform iterative calculation updates according to the coordinates of the atoms in the updated input molecules until the calculation upper limit is reached or the distance between the splicing sites of several input molecules meets the set value, stop the iterative calculation update, and output the final structure after splicing several input molecules.

[0129] In this embodiment, in the initial conformation generation and optimization module 001, in the process of generating the initial conformation of the input molecule according to the bond connection relationship of atoms in the input molecule through the molecular structure generation strategy, the molecular structure generation strategy includes systematic search, model construction, random search, distance geometry, molecular dynamics, and Monte Carlo strategy;

[0130] In the process of structurally optimizing the initial conformation of the input molecule by the energy-based optimization algorithm, the energy-based optimization algorithm includes a molecular energy calculation strategy and an optimization algorithm;

[0131] The molecular energy calculation strategies include: molecular force field strategy and semi-empirical strategy; wherein the semi-empirical strategy includes DFTB, xTB, PM6, PM7;

[0132] The optimization algorithms include: conjugate gradient method, Newton method and steepest descent method.

[0133] In this embodiment, in the molecular moment of inertia and total mass calculation module 003, in the process of calculating the moment of inertia and the total mass of the input molecule by setting the calculation strategy, when calculating the moment of inertia, the mass of the atom is set to the relative atomic mass; the calculation formula of the moment of inertia is:

[0134]

[0135] Where I is the calculated moment of inertia, i is the number of the atom, and m is i is the relative atomic mass of the ith atom; R i is the distance of the ith atom from the rotation axis, where the rotation axis is defined as the vector pointing in the direction of the torque through the center of mass of the molecule.

[0136] In this embodiment, in the interaction force calculation module 004, the calculation formula of the interaction force between atoms of a number of input molecules is:

[0137]

[0138] In the formula, is the interaction potential between the i-th and j-th atoms, r ij is the distance between the i-th and j-th atoms.

[0139] In this embodiment, in the atomic coordinate updating module 005, in the process of calculating the translational displacement and the rotational displacement of the input molecule according to the force and torque passing through the center of mass of the input molecule, the calculation formula of the translational displacement is:

[0140]

[0141] In the formula, F 1 is the force passing through the molecular mass center; M is the mass of the molecule; x is the translational displacement;

[0142] The calculation formula of the rotation displacement is:

[0143]

[0144] Where θ is the rotational displacement; τ is the torque; and I is the moment of inertia.

[0145] In this embodiment, in the final structure output module 006, when the distance between the splicing sites of a number of input molecules meets the set value, the iterative calculation and updating process is stopped, and the calculation formula for the distance between the splicing sites is:

[0146]

[0147] Where d is the distance between splicing sites; x 1 and x 2 Represents the geometric coordinates of splice site 1 and splice site 2.

[0148] It should be noted that the information interaction, execution process and other contents between the modules of the above-mentioned system are based on the same concept as the method embodiment in Example 1 of the present application, and the technical effects they bring are the same as those of the method embodiment of the present application. For specific contents, please refer to the description in the method embodiment shown above in the present application, and will not be repeated here.

[0149] Example 3

[0150] Embodiment 3 of the present invention provides a non-transitory computer-readable storage medium, in which a program code for a method for generating an initial structure of a small molecule transition state based on conformation and force field is stored. The program code includes instructions for executing the method for generating an initial structure of a small molecule transition state based on conformation and force field of Embodiment 1 or any possible implementation thereof.

[0151] The computer-readable storage medium may be any available medium that can be accessed by a computer or a data storage device such as a server or a data center that includes one or more available media. The available medium may be a magnetic medium (e.g., a floppy disk, a hard disk, a tape), an optical medium (e.g., a DVD), or a semiconductor medium (e.g., a solid-state drive (SSD)).

[0152] Example 4

[0153] Embodiment 4 of the present invention provides an electronic device, including: a memory and a processor;

[0154] The processor and the memory communicate with each other via a bus; the memory stores program instructions that can be executed by the processor, and the processor calls the program instructions to execute the method for generating initial structure of small molecule transition state based on conformation and force field of Example 1 or any possible implementation thereof.

[0155] Specifically, the processor can be implemented by hardware or by software. When implemented by hardware, the processor can be a logic circuit, an integrated circuit, etc.; when implemented by software, the processor can be a general-purpose processor implemented by reading software codes stored in a memory. The memory can be integrated in the processor or can be located outside the processor and exist independently.

[0156] In the above embodiments, it can be implemented in whole or in part by software, hardware, firmware or any combination thereof. When implemented using software, it can be implemented in whole or in part in the form of a computer program product. The computer program product includes one or more computer instructions. When the computer program instructions are loaded and executed on a computer, the process or function described in the embodiment of the present invention is generated in whole or in part. The computer can be a general-purpose computer, a special-purpose computer, a computer network, or other programmable systems. The computer instructions can be stored in a computer-readable storage medium, or transmitted from a computer-readable storage medium to another computer-readable storage medium, for example, the computer instructions can be transmitted from a website site, computer, server or data center by wired (e.g., coaxial cable, optical fiber, digital subscriber line (DSL)) or wireless (e.g., infrared, wireless, microwave, etc.) mode to another website site, computer, server or data center.

[0157] Obviously, those skilled in the art should understand that the above modules or steps of the present invention can be implemented by a general computing system, they can be concentrated on a single computing system, or distributed on a network composed of multiple computing systems, and optionally, they can be implemented by a program code executable by a computing system, so that they can be stored in a storage system and executed by the computing system, and in some cases, the steps shown or described can be executed in a different order than here, or they can be made into individual integrated circuit modules, or multiple modules or steps therein can be made into a single integrated circuit module for implementation. Thus, the present invention is not limited to any specific combination of hardware and software.

[0158] Although the present invention has been described in detail above by general description and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements can be made to the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all belong to the scope of protection claimed by the present invention.

Claims

1. A method for generating initial structures of small molecule transition states based on conformation and force fields, characterized in that: include: Determine the bond connection relationship of atoms in the input molecule through the input SMILES; generate an initial conformation of the input molecule through a molecular structure generation strategy based on the bond connection relationship of atoms in the input molecule; perform structural optimization on the initial conformation of the input molecule through an energy-based optimization algorithm; According to the charge information of atoms in the input molecules or the charge information of the electrostatic potential on the surface of the input molecules, the positions where the input molecules attract each other are determined; according to the positions where the input molecules attract each other, the input molecules are rotated and translated to determine the relative orientation of the input molecules, thereby completing the initialization of the splicing structure of the input molecules; By setting the calculation strategy, the moment of inertia and total mass of the input molecule are calculated; According to the interaction potential between atoms and the interaction potential between splicing sites, the interaction forces between atoms of a number of input molecules and the interaction forces between splicing sites of a number of input molecules are calculated; Decomposing the interaction force between atoms on each atom in the input molecule into a force and a torque passing through the center of mass of the input molecule; calculating the translational displacement and the rotational displacement of the input molecule according to the force and the torque passing through the center of mass of the input molecule; updating the coordinates of the atoms in the input molecule according to the translational displacement and the rotational displacement of the input molecule; According to the coordinates of the atoms in the updated input molecules, iterative calculation and updating are performed until the calculation upper limit is reached or the distance between the splicing sites of several input molecules meets the set value, the iterative calculation and updating are stopped, and the final structure after the splicing of several input molecules is output; The calculation formula for the interaction force between atoms of several input molecules is: In the formula, is the interaction potential between the i-th and j-th atoms, r ij is the distance between the i-th and j-th atoms.

2. The method for generating the initial structure of a small molecule transition state based on conformation and force field according to claim 1, characterized in that: In the process of generating the initial conformation of the input molecule according to the bond connection relationship of atoms in the input molecule through the molecular structure generation strategy, the molecular structure generation strategy includes systematic search, model construction, random search, distance geometry, molecular dynamics, and Monte Carlo strategy.

3. The method for generating the initial structure of a small molecule transition state based on conformation and force field according to claim 2, characterized in that: In the process of structurally optimizing the initial conformation of the input molecule by the energy-based optimization algorithm, the energy-based optimization algorithm includes a molecular energy calculation strategy and an optimization algorithm; The molecular energy calculation strategies include: molecular force field strategy and semi-empirical strategy; wherein the semi-empirical strategy includes DFTB, xTB, PM6, PM7; The optimization algorithms include: conjugate gradient method, Newton method and steepest descent method.

4. The method for generating the initial structure of a small molecule transition state based on conformation and force field according to claim 3, characterized in that: In the process of calculating the moment of inertia and the total mass of the input molecule by setting the calculation strategy, when calculating the moment of inertia, the mass of the atom is set to the relative atomic mass; the calculation formula of the moment of inertia is: Where I is the calculated moment of inertia, i is the number of the atom, and m is i is the relative atomic mass of the ith atom; R i is the distance of the ith atom from the rotation axis, where the rotation axis is defined as the vector pointing in the direction of the torque through the center of mass of the molecule.

5. The method for generating the initial structure of a small molecule transition state based on conformation and force field according to claim 4, characterized in that: In the process of calculating the translational displacement and the rotational displacement of the input molecule according to the force and torque passing through the center of mass of the input molecule, the calculation formula of the translational displacement is: Where F1 is the force passing through the center of mass of the molecule; M is the mass of the molecule; x is the translational displacement; The calculation formula of the rotation displacement is: Where θ is the rotational displacement; τ is the torque; and I is the moment of inertia.

6. The method for generating the initial structure of a small molecule transition state based on conformation and force field according to claim 5, characterized in that: When the distance between the splicing sites of several input molecules meets the set value, the iterative calculation and update process is stopped. The calculation formula for the distance between the splicing sites is: Where d is the distance between the splicing sites; x1 and x2 represent the geometric coordinates of splicing site 1 and splicing site 2.

7. A device for generating initial structure of transition state of small molecule based on conformation and force field, adopting the method for generating initial structure of transition state of small molecule based on conformation and force field according to any one of claims 1 to 6, characterized in that: include: The initial conformation generation and optimization module is used to determine the bond connection relationship of atoms in the input molecule through the input SMILES; generate the initial conformation of the input molecule through the molecular structure generation strategy according to the bond connection relationship of atoms in the input molecule; and perform structural optimization on the initial conformation of the input molecule through the energy-based optimization algorithm; The molecular splicing structure initialization module is used to determine the positions of mutual attraction between input molecules according to the charge information of atoms in the input molecules or the charge information of the electrostatic potential on the surface of the input molecules; according to the positions of mutual attraction between the input molecules, the input molecules are rotated and translated to determine the relative orientation of the input molecules, thereby completing the initialization of the input molecular splicing structure; The molecular moment of inertia and total mass calculation module is used to calculate the moment of inertia and total mass of the input molecule by setting the calculation strategy; An interaction force calculation module, used for calculating the interaction forces between atoms of a plurality of input molecules and the interaction forces between splicing sites of a plurality of input molecules according to the interaction potential between atoms and the interaction potential between splicing sites; an atomic coordinate updating module, for decomposing the interaction force between atoms on each atom in the input molecule into a force and a torque passing through the center of mass of the input molecule; calculating the translational displacement and the rotational displacement of the input molecule according to the force and the torque passing through the center of mass of the input molecule; and updating the coordinates of the atoms in the input molecule according to the translational displacement and the rotational displacement of the input molecule; The final structure output module is used to perform iterative calculation and update according to the coordinates of atoms in the updated input molecules until the calculation upper limit is reached or the distance between the splicing sites of several input molecules meets the set value, stop the iterative calculation and update, and output the final structure after the splicing of several input molecules; The calculation formula for the interaction force between atoms of several input molecules is: In the formula, is the interaction potential between the i-th and j-th atoms, r ij is the distance between the i-th and j-th atoms.

8. The device for generating initial structure of transition state of small molecule based on conformation and force field according to claim 7, characterized in that: In the initial conformation generation and optimization module, in the process of generating the initial conformation of the input molecule according to the bond connection relationship of atoms in the input molecule through the molecular structure generation strategy, the molecular structure generation strategy includes systematic search, model construction, random search, distance geometry, molecular dynamics, and Monte Carlo strategy; In the process of structurally optimizing the initial conformation of the input molecule by the energy-based optimization algorithm, the energy-based optimization algorithm includes a molecular energy calculation strategy and an optimization algorithm; The molecular energy calculation strategies include: molecular force field strategy and semi-empirical strategy; wherein the semi-empirical strategy includes DFTB, xTB, PM6, PM7; The optimization algorithms include: conjugate gradient method, Newton method and steepest descent method.

9. The device for generating initial structure of transition state of small molecule based on conformation and force field according to claim 8, characterized in that: In the molecular moment of inertia and total mass calculation module, in the process of calculating the moment of inertia and the total mass of the input molecule by setting the calculation strategy, when calculating the moment of inertia, the mass of the atom is set to the relative atomic mass; the calculation formula of the moment of inertia is: Where I is the calculated moment of inertia, i is the number of the atom, and m is i is the relative atomic mass of the ith atom; R i is the distance of the ith atom from the rotation axis, where the rotation axis is defined as the vector pointing in the direction of the torque through the center of mass of the molecule.

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