WO2022036538A1

WO2022036538A1 - Organic molecular crystal construction method and system

Info

Publication number: WO2022036538A1
Application number: PCT/CN2020/109713
Authority: WO
Inventors: 师雪坤; 马健; 温书豪; 赖力鹏
Original assignee: 深圳晶泰科技有限公司
Priority date: 2020-08-18
Filing date: 2020-08-18
Publication date: 2022-02-24

Abstract

An organic molecular crystal construction method and system, comprising: receiving a crystal parameter to generate a crystal, generating a crystal file according to a set format, forming core crystal data, and storing the core crystal data into a crystal database; invoking, according to a crystal structure and a preset energy accuracy, a corresponding crystal energy calculation algorithm to calculate crystal energy; and performing optimization according to the crystal structure and the calculated crystal energy, outputting a crystal parameter adjustment value according to an optimization algorithm rule, adjusting the crystal parameter and transferring same to the crystal generation step to generate a new crystal such that an initial crystal and a series of crystals obtained by one or more optimizations form an evolutionary relation, and storing mutual evolution information between the crystals into the crystal database. The organic molecular crystal construction method and system perform optimization by means of crystal evolution according to a crystal structure and crystal energy, adjust a crystal parameter according to an optimization algorithm and transfer same to a crystal generation step for iteration, and obtain a crystal structure having better properties by means of iterative optimizations.

Description

Organic molecular crystal construction method and system

technical field

The invention relates to a method for constructing and generating molecular crystals, in particular to a method and system for constructing organic molecular crystals.

Background technique

Organic molecular crystals are widely used in many fields such as medicine, daily chemical products, and energetic materials. For a given organic molecule, how to quickly design a crystal structure with better properties directly determines the speed and success rate of product development. The traditional method is to rely on large-scale screening of experiments to find different crystal structures through the combination of a large number of different experimental conditions, and then select the ones with better relative properties. In recent years, with the rapid improvement of computing power, the method of simulating crystal structure and properties by calculation has been developed rapidly. The current computational simulation methods mainly rely on global search and local optimization algorithm modules to automatically generate and optimize crystal structures, and use the algorithm modules to screen out crystal structures with better properties.

Traditional experimental methods cannot accurately design crystals at the microscopic molecular scale, and can only rely on macroscopic experimental experience to combine a large number of experimental conditions and experimental methods to find crystal structures with better properties. The problem with this is that the whole process is relatively blind, because there are many experimental conditions that can be tried, and different combinations of solvent combinations, temperature, humidity, pressure, and changes of these factors over time may result in new crystal structures, and may also be repeated. crystal structure or no crystal. Therefore, the efficiency of the whole method is relatively low, and the selected crystal structure is only the optimal solution within the range found by the experiment. If it is among all possible crystal structures, it is probably not the optimal solution.

Current computational simulation methods are a significant improvement over traditional experimental methods. Because through computer virtual screening, hundreds of millions of crystal structures can be directly stacked, and then the properties of these crystal structures can be calculated. In this way, better crystal structures can be found in a very large-scale crystal space. However, it is very difficult to find a better crystal structure in such a large crystal space simply by using the algorithm, which puts forward very high requirements for the algorithm's ability to search in the crystal space of a given molecule. It also places very high demands on computing resources. For relatively simple organic molecules, such computational simulation methods have performed well. However, for complex problems with more than 10 flexible angles or more than 3 different molecules in the unit cell, the performance of current computational simulation methods is relatively poor.

SUMMARY OF THE INVENTION

Based on this, it is necessary to provide an organic molecular crystal construction method that can optimize the generated crystal structure.

At the same time, an organic molecular crystal construction system that can optimize the generated crystal structure is provided.

An organic molecular crystal construction method, comprising:

Crystal generation: receive crystal parameters to generate crystals, generate crystal files according to the set format, form core crystal data, and store the core crystal data in the crystal database;

Crystal energy calculation: call the corresponding crystal energy calculation algorithm to calculate the crystal energy according to the crystal structure and the preset energy accuracy;

Crystal evolution: optimize based on crystal structure and calculated crystal energy, output crystal parameter adjustment values according to optimization algorithm rules, adjust crystal parameters and transfer to crystal generation step, generate new crystals, initial crystals and one or more optimized series of crystals The evolution relationship is formed, and the mutual evolution information between crystals is stored in the crystal database.

In a preferred embodiment, it also includes: real-time monitoring of crystal evolution: retrieving the generated crystal structure in real time, retrieving the crystal structure in the crystal database, and crystal parameter adjustment values during the crystal evolution process; the crystal parameters include: crystal every time The molecular SMILES formula of each component, the angle of each flexible angle of each molecule, the unit cell parameters, the position of the centroid of each molecule in the unit cell, the orientation of each molecule in the unit cell; the crystal generation includes: artificial Crystal generation: receive crystal parameter input commands or crystal parameter adjustment input commands, and generate crystals according to the input parameters.

In a preferred embodiment, the crystal generation further includes: automatic crystal generation: generating crystal parameters according to a specified target molecule or adjusting parameters according to parameter adjustment values of the crystal to generate a new crystal, and judging the rationality of generating a new crystal, if If the rationality judgment is passed, the crystal is successfully generated. If the rationality judgment is not passed, the crystal parameters are adjusted to regenerate the crystal.

In a preferred embodiment, the rationality judgment includes: judging whether the distance between two atoms in the crystal conforms to chemical rules, and judging whether the density of the crystal is within a given density range.

In a preferred embodiment, judging whether the chemical rules are met includes: judging whether the distance and bond angle between any two atoms in the same molecule are equal to the initial input or the adjusted input distance and distance between the two atoms in the molecule. Bond angle, to determine whether the distance between two atoms of different molecules is not less than the van der Waals radius; the setting of the density interval includes: for each molecule of asymmetric unit, randomly select an atom as the origin, according to the distance between the atoms in the molecule Calculate the coordinates of each atom relative to the origin using the bond length and bond angle of Density interval, where a, b are preset.

In a preferred embodiment, if the chemical rules are not met, the distance between the centroids of the molecules is adjusted, and the distance between the centroids is expanded according to a preset coefficient. ; If it is judged that the density of the crystal exceeds the lower limit of the density interval, expand the distance between the centroids according to the preset coefficient; if the density of the crystal exceeds the upper limit of the density interval, reduce the side length of the unit cell according to the set coefficient, and iterate until the crystal The density is within the density range.

In a preferred embodiment, the unit cell parameters, the space group, the relative coordinate values of the atoms in each asymmetric unit molecule in the unit cell are obtained, and the work is performed under the specified space group, and the input crystal parameters are adjusted or adjusted according to the input crystal parameters. The parameter calculates the relative coordinate value of each atom in the unit cell: for each molecule of asymmetric unit, randomly select an atom as the origin, and calculate the relative coordinate value of each atom relative to the origin according to the bond length and bond angle between the atoms in the molecule. Coordinate, determine the rotatable flexible angle according to the input crystal parameters or adjust the input crystal parameters, calculate the position of the center of mass of the molecule according to the coordinate position of each atom, and determine the position of the center of mass by the weighted average of the atomic mass and the spatial position, and calculate the position of the two atoms The distance between, take the vector of the two atoms with the longest distance so far as the orientation of the molecule, use the three-dimensional space transformation to transform the centroid and orientation of the molecule to the input crystal parameters or adjust the coordinates and orientation of the given centroid in the input crystal parameters , to obtain the transformed coordinate value of each atom as the relative coordinate value of the atoms in the molecule in the unit cell to generate a crystal; or to obtain the unit cell parameters and the relative coordinates of each atom in the unit cell according to the crystal structure, According to the coordinates of each atom, the flexible angle in the molecule, the centroid text of the molecule and the vector orientation between the two atoms with the longest distance in the molecule are calculated, and the crystal is generated according to the crystal structure and adjusting the input parameters.

In a preferred embodiment, the crystal database includes a file database and a graph database, the crystal data includes a crystal file and each adjustment parameter, the crystal file includes a CIF file, and the crystal file is stored in the file In the database, the evolution information is recorded as a tree structure, the ID of the parent crystal is recorded for each crystal structure, the parent crystal ID of the initial crystal is empty, the evolution relationship is stored in the graph database, and the crystal evolution step includes: : Take the crystal energy as the optimization goal or the crystal structure density as the optimization goal, use the particle swarm optimization algorithm or the Monte Carlo optimization algorithm to iteratively optimize the crystal structure, obtain the crystal structure and the calculated crystal energy, and use the particle swarm optimization algorithm or Monte Carlo optimization algorithm to optimize the crystal structure. The algorithm outputs the crystal parameter adjustment value, and transfers to the crystal generation step.

In a preferred embodiment, in the iterative optimization in the crystal evolution step, the initial minimum energy is 0, the number of falling steps for recording the lowest energy is 0, and each parameter of the obtained crystal is randomly fluctuated for the initial crystal according to the optimization algorithm, A new crystal is obtained, and iterates according to the preset number of iterations. If the crystal energy is the optimization goal, each evolution iteration compares the energy of the current crystal structure with the lowest recorded energy. If the current energy is lower, the lowest energy of the system is recorded. is the current energy, and the minimum energy iteration number is recorded as 0. If the current energy is high, the minimum energy iteration number +1 is added, and if the iteration number exceeds the preset number of iterations, it will stop;

If the crystal density is the optimization goal, set the initial minimum density as the upper limit of the density interval, and record the minimum density iteration steps as 0. Each evolution iteration will compare the density of the current crystal structure with the recorded minimum density. If the current density is lower , the lowest density of the system is recorded as the current density, and the number of iteration steps of the lowest density is recorded as 0. If the current density is high, the number of iteration steps of the lowest density is +1, and if the number of iteration steps exceeds the preset number of iterations, it will stop;

The crystal energy calculation includes: a force field-accurate crystal energy calculation method for calculating the crystal energy with a force field according to the crystal structure and its corresponding force field, or a semi-empirical precision crystal energy calculation method for calculating the crystal energy according to the crystal structure and its corresponding semi-empirical method, Or a high-precision quantitative crystal energy calculation method based on the crystal structure and its corresponding crystal energy calculated by a high-precision quantitative method.

An organic molecular crystal construction system comprising:

Crystal generation module: receive crystal parameters to generate crystals, generate crystal files according to the set format, form core crystal data, and store the core crystal data in the crystal database;

Crystal energy calculation module: call the corresponding crystal energy calculation algorithm to calculate the crystal energy according to the crystal structure and the preset energy precision;

Crystal evolution module: optimize according to crystal structure and calculated crystal energy, output crystal parameter adjustment values according to optimization algorithm rules, adjust crystal parameters and transfer to crystal generation step, generate new crystal, initial crystal and a series of one or more optimizations The crystals form an evolution relationship, and the mutual evolution information between crystals is stored in the crystal database.

The above-mentioned organic molecular crystal construction method and system are optimized according to the crystal structure and crystal energy through crystal evolution, and the crystal parameters are adjusted according to the optimization algorithm and transferred to the crystal generation step for iteration, and a crystal structure with better properties is obtained through iterative optimization. And store the evolution relationship of the crystal to track the evolution process of the crystal, and modify the crystal parameters according to the evolution process for optimization.

In addition, crystal evolution obtains the crystal structure for the first time during the operation, and adjusts the crystal structure parameters randomly, and stores the crystal structure and the adjusted value in the crystal database. If the crystal structure has been input into the crystal evolution process during the system operation, the crystal structure parameters will be adjusted according to the preset particle swarm or Monte Carlo search algorithm. The user can preset the algorithm to be used through the interface. This module will automatically transfer the crystal structure and adjustment parameters to the crystal generation step; the crystal generation step will automatically generate a new crystal structure, then transfer it to the crystal energy calculation process, and then transfer it to the crystal evolution process for cyclic iteration. During the cycle, the user can retrieve the latest evolution structure information and evolution history data through the crystal evolution real-time monitoring module. The user can manually adjust the parameters of one or more of the crystal structures based on experience, and transfer the adjusted structure to the artificial crystal generation module. In this way, the cyclic process of crystal evolution continues from the artificially adjusted crystal. The whole system supports multiple evolution loops working simultaneously.

Description of drawings

Fig. 1 is the flow chart of the organic molecular crystal construction method of one embodiment of the present invention;

2 is a block diagram of an organic molecular crystal construction system according to an embodiment of the present invention;

FIG. 3 is a block diagram of an organic molecular crystal construction system according to a preferred embodiment of the present invention.

detailed description

As shown in Figure 1, the method for constructing an organic molecular crystal according to an embodiment of the present invention includes:

Step S101, crystal generation: receiving crystal parameters to generate crystals, and generating crystal files according to the set format, forming core crystal data, and storing the core crystal data in the crystal database;

Step S103, crystal energy calculation: call the corresponding crystal energy calculation algorithm to calculate the crystal energy according to the crystal structure and the preset energy precision;

Step S105, crystal evolution: optimize according to the crystal structure and the calculated crystal energy, output the crystal parameter adjustment value according to the optimization algorithm rule, adjust the crystal parameters and transfer to the crystal generation step, generate a new crystal, the initial crystal and one or more optimizations The series of crystals form an evolution relationship, and the mutual evolution information between crystals is stored in the crystal database.

The organic molecular crystal construction method of the present invention further comprises: real-time monitoring of crystal evolution: real-time retrieval of the generated crystal structure, retrieval of the crystal structure in the crystal database and crystal parameter adjustment values during the crystal evolution process.

The crystal parameters of the present invention include: the molecular SMILES formula of each component of the crystal, the angle of each flexible angle of each molecule, the unit cell parameters, the position of the centroid of each molecule in the unit cell, the position of each molecule in the unit cell towards;

The crystal generation step of the present invention includes one or more of artificial crystal generation and automatic crystal generation.

IOL generation: receive crystal parameter input commands or crystal parameter adjustment input commands, and generate crystals according to the input parameters.

Crystal parameters include: molecular SMILES formula of each component of the crystal, angle of each flexible angle of each molecule (θ ₁₁ , θ ₁₂ , ..., θ _1n ), (θ ₂₁ , θ ₂₂ , ..., θ _2n ), ... , ( _θ _m1 _, _θ _m2 , _. , (x ₂ , y ₂ , z ₂ ), …, (x _m , y _m , z _m ), the orientation of each molecule in the unit cell

An interface can be provided to allow users to directly input the above parameters, and the module will directly generate virtual crystals based on these parameters. θ represents the flexibility angle in the molecule, that is, the dihedral angle corresponding to the rotatable single bond in the molecule. α, β, and γ are the angles between the three sides at the origin of the unit cell, and a, b, and c are the lengths of the three sides. The centroid position (x _m , y _m , z _m ) represents the spatial coordinates of the centroid of the m-th molecule, the orientation in the unit cell

Indicates the angle between the vector formed by the two farthest atoms within the molecule of the mth molecule and the three coordinate axes.

Modify the parameters of existing crystals in the crystal database to generate new crystal structures. An interface can be provided for the user to read the structure in the crystal database. The user can directly modify one or more of the above crystal parameters through the interface, and the module will generate a virtual crystal according to the new parameters.

Automatic crystal generation: Generate crystal parameters according to the specified target molecule or adjust parameters according to the crystal parameter adjustment value to generate new crystals, and make a rational judgment on the generation of new crystals. If the rationality judgment is passed, the crystal will be successfully generated. If the judgment is made, the crystal parameters are adjusted to regenerate the crystal.

Specifically, the crystal structure is randomly generated. For the specified target molecule, the module can automatically generate the above crystal parameters, and then make a rational judgment on the newly generated crystal. If the rationality judgment is passed, the crystal is successfully generated. If the rationality judgment is not passed, the crystal parameters are adjusted to regenerate the crystal until a reasonable crystal structure is generated. The user can limit the number of reasonable crystal attempts through the interface provided by the system.

In addition, the given crystal structure is adjusted to obtain a new crystal structure. The module receives the crystal structure and the parameters to be adjusted, and then generates a new crystal with the adjusted parameters. If the rationality judgment is passed, the crystal is successfully generated. If the rationality judgment is not passed, the crystal parameters are adjusted to regenerate the crystal until a reasonable crystal structure is generated. The user can limit the number of reasonable crystal attempts through the interface provided by the system.

Further, the rationality judgment of this embodiment includes: judging whether the distance between two atoms in the crystal complies with chemical rules, and judging whether the density of the crystal is within a given density range.

Judging whether it complies with chemical rules includes: judging whether the distance and bond angle between any two atoms in the same molecule are equal to the initial input between the two atoms in the molecule or adjusting the input distance and bond angle, and judging the difference between different molecules. Whether the distance between two atoms is not less than the van der Waals radius; the setting of the density interval includes: for each molecule of asymmetric unit, randomly select an atom as the origin, and calculate according to the bond length and bond angle between the atoms in the molecule The coordinates of each atom relative to the origin, use the mass of each atom and the position of each atom to calculate the density d of the molecule in space, and set the density interval of the crystal with [a*d,b*d], where a, b Make settings in advance.

If it does not conform to the chemical rules, adjust the distance between the centroids of the molecules and expand the distance between the centroids according to the preset coefficient. If it still does not meet the rules after adjustment, continue to expand the distance between the centroids until it conforms; if it is judged that the density of the crystal exceeds the When the lower limit of the density interval is reached, the distance between the centroids is expanded by the preset coefficient; if the density of the crystal exceeds the upper limit of the density interval, the side length of the unit cell is reduced by the set coefficient, and it is iterated until the density of the crystal reaches the range of the density interval.

To generate a crystal, it is necessary to obtain the unit cell parameters, space group, and the relative coordinate values of the atoms in each asymmetric unit molecule in the unit cell, work under the specified space group, and calculate each according to the input crystal parameters or adjust the input crystal parameters. The relative coordinate value of the atom in the unit cell: For each molecule of asymmetric unit, randomly select an atom as the origin, and calculate the coordinate of each atom relative to the origin according to the bond length and bond angle between the atoms in the molecule, according to the input Determine the rotatable flexible angle by adjusting the crystal parameters or adjust the input crystal parameters, calculate the position of the center of mass of the molecule according to the coordinate position of each atom, determine the position of the center of mass by the weighted average of the atomic mass and the spatial position, and calculate the distance between two atoms , take the vector of the two atoms with the longest distance so far as the orientation of the molecule, and use the three-dimensional space transformation to transform the centroid and orientation of the molecule to the input crystal parameters or adjust the coordinates and orientation of the given centroid in the input crystal parameters to obtain each The transformed coordinate value of the atom is used as the relative coordinate value of the atoms in the molecule in the unit cell to generate a crystal; or the unit cell parameters and the relative coordinates of each atom in the unit cell are obtained according to the crystal structure. The coordinates of the calculation calculate the flexible angle in the molecule, the centroid text of the molecule and the vector orientation between the two atoms with the longest distance in the molecule, and generate the crystal according to the crystal structure and adjusting the input parameters.

Crystal databases include: file databases and graph databases. Crystal data includes: crystal file and adjustment parameters for each time. The crystal files of this embodiment include: CIF files. Generating a crystal requires determining the unit cell parameters in the CIF file describing the crystal, the space group, and the relative most coordinate values in the unit cell of the atoms in the molecules of each asymmetric unit. After inputting the above parameters, the system will directly use the unit cell parameters in the parameters. There are 230 space groups in total, which are preset and the system works under the specified space group.

The crystal files of this embodiment are stored in the file database. The evolution information is recorded as a tree structure, and the ID of the parent crystal is recorded for each crystal structure, and the parent crystal ID of the initial crystal is empty. Evolutionary relationships are stored in a graph database.

The crystal evolution step also includes: taking the crystal energy as the optimization goal or the crystal structure density as the optimization goal, using the particle swarm optimization algorithm or the Monte Carlo optimization algorithm to iteratively optimize the crystal structure, obtaining the crystal structure and the calculated crystal energy, according to the particle swarm optimization algorithm. Or the Monte Carlo optimization algorithm outputs the crystal parameter adjustment value, and transfers to the crystal generation step.

In the iterative optimization in the crystal evolution step, the initial minimum energy is 0, the number of falling steps to record the lowest energy is 0, and each parameter of the obtained crystal is randomly fluctuated for the initial crystal according to the optimization algorithm to obtain a new crystal, according to the preset If the crystal energy is used as the optimization goal, the energy of the current crystal structure is compared with the lowest recorded energy in each evolution iteration. If the current energy is lower, the lowest energy of the system is recorded as the current energy, and the lowest energy iteration steps are The record is 0. If the current energy is high, the number of iteration steps for the lowest energy is +1, and if the number of iteration steps exceeds the preset number of iterations, it will stop.

Further, the crystal energy calculation in this embodiment includes: a force field precision crystal energy calculation method for calculating crystal energy using a force field according to the crystal structure and its corresponding crystal structure, or a semi-empirical precision crystal for calculating crystal energy using a semi-empirical method according to the crystal structure and its corresponding semi-empirical method. An energy calculation method, or a high-precision quantized crystal energy calculation method based on the crystal structure and its corresponding crystal energy calculated by a high-precision quantitative method.

The force field precision crystal energy calculation method supports the fast calculation of the energy of the crystal structure with the force field. Input a crystal structure, and the force field precision crystal energy calculation method will output the crystal structure and its corresponding crystal energy calculated by force field. Commonly used calculation tools for force field precision crystal energy calculation methods include Amber, charmm, etc.

Semi-empirical precision crystal energy calculation method, which supports the calculation of the energy of crystal structures with semi-empirical methods (such as DFTB). Input a crystal structure, and the module will output the crystal structure and its corresponding crystal energy calculated by the semi-empirical method. The calculation tools of the semi-empirical precision crystal energy calculation method include DFTB and Dmacrys.

The high-precision quantitative crystal energy calculation method supports the use of high-precision quantitative methods (such as DFT) to calculate the energy of the crystal structure. Inputting a crystal structure, using the high-precision quantitative crystal energy calculation method will output the crystal structure and its corresponding crystal energy calculated by the high-precision quantitative method. The calculation tools for high-precision quantitative crystal energy calculation methods include VASP, Crystal09, etc.

As shown in FIG. 2, an organic molecular crystal construction system 100 according to an embodiment of the present invention includes:

Crystal generation module 20: generate crystals by receiving crystal parameters, generate crystal files according to the set format, form core crystal data, and store the core crystal data in the crystal database 80;

The crystal energy calculation module 40: according to the crystal structure and the preset energy precision, the corresponding crystal energy calculation algorithm is invoked to calculate the crystal energy;

Crystal evolution module 60: perform optimization according to the crystal structure and the calculated crystal energy, output the crystal parameter adjustment values according to the optimization algorithm rules, adjust the crystal parameters and transfer to the crystal generation step, generate a new crystal, the initial crystal is the same as the one or more optimized ones. The series of crystals form an evolution relationship, and the mutual evolution information between the crystals is stored in the crystal database 80 .

As shown in FIG. 3 , further, the crystal generation module 20 in this embodiment includes: an artificial crystal generation module 22 and an automatic crystal generation module 24 .

The intraocular lens generation module 22 of this embodiment. There are two ways to generate crystals. Enter crystal parameters to build crystals directly. Crystal parameters include: molecular SMILES formula of each component of the crystal, angle of each flexible angle of each molecule (θ ₁₁ , θ ₁₂ , ..., θ _1n ), (θ ₂₁ , θ ₂₂ , ..., θ _2n ), ... , ( _θ _m1 _, _θ _m2 , _. , (x ₂ , y ₂ , z ₂ ), …, (x _m , y _m , z _m ), the orientation of each molecule in the unit cell

The module provides an interface to allow users to directly input the above parameters, and the module will directly generate virtual crystals according to these parameters; modify the parameters of existing crystals in the crystal database to generate new crystal structures. This module provides an interface for users to read the structure in the crystal database. Users can directly modify one or more of the above crystal parameters through the interface, and the module will generate virtual crystals according to the new parameters. After the module generates crystals, it will generate crystal files according to the CIF standard format for use by other modules in the system.

SMILES (Simplified molecular input line entry specification), simplified molecular linear input specification, is a specification that explicitly describes the molecular structure with ASCII strings. SMILES uses a string of characters to describe a three-dimensional chemical structure, and it must convert the chemical structure into a spanning tree. This system adopts the vertical priority traversal tree algorithm. During the transformation, the hydrogen must be removed first, and the ring must be opened. When denoting, the atoms at the ends of the bonds to be removed should be marked with numbers, and the branches should be written in parentheses. SMILES strings can be imported and converted into 2D graphics or 3D models of molecules by most molecular editing software. Converting to two-dimensional graphics can use Helson's "Structure Diagram Generation algorithm" (Structure Diagram Generation algorithm).

The automatic crystal generation module 24 of this embodiment can automatically generate crystal structures. There are two ways to generate it. The crystal structure is randomly generated. For the specified target molecule, the module can automatically generate the above crystal parameters, and then make a rational judgment for the newly generated crystal. If the rationality judgment is passed, the crystal is successfully generated. If the rationality judgment is not passed, the crystal parameters are adjusted to regenerate the crystal until a reasonable crystal structure is generated. The user can limit the number of reasonable crystal attempts through the interface provided by the system. The given crystal structure is adjusted to obtain a new crystal structure. This module receives the crystal structure and the parameters that need to be adjusted, and then generates a new crystal with the adjusted parameters. If the rationality judgment is passed, the crystal is successfully generated. If the rationality judgment is not passed, the crystal parameters are adjusted to regenerate the crystal until a reasonable crystal structure is generated. The user can limit the number of reasonable crystal attempts through the interface provided by the system.

The criteria for reasonable judgment are as follows:

The distance between two atoms in the crystal needs to comply with chemical rules;

The density of the crystal needs to be within the given density interval.

After the module generates crystals, it will generate crystal files according to the CIF standard format for use by other modules in the system.

Chemical rules for reasonable judgment: 1. The distance and bond angle between two atoms in the same molecule are equal to the initial input distance and bond angle of the molecule; 2. The distance between two atoms of different molecules is not less than the van der Waals radius.

The density interval setting method of the crystal is as follows: 1. For each molecule of asymmetric unit, randomly select an atom as the origin, and calculate the coordinates of each atom relative to the origin according to the bond length and bond angle between the atoms in the molecule. The rotatable flexible angle is determined according to the value in the input parameter; 2. Calculate the density d of the molecule in space with the mass of each atom and the position of each atom; 3. Set with [a*d,b*d] The density interval of the crystal, where a, b can be preset according to the user's needs and experience.

The specific process of judging the rationality: first calculate the distance between atoms in the same molecule, the standard value of bond angle, the minimum value between two atoms in the molecule, and the density interval; for each generated virtual crystal structure, calculate the same molecule The distance and bond angle between atoms within a molecule, the distance and density between two atoms in a molecule. ; Compare with the first calculated value one by one, if it matches, judge that the crystal is reasonable, if there is a piece of data that does not match, judge that the crystal is unreasonable.

If the chemical rules do not meet the rules, the distance between the centroids of the molecules will be adjusted first. The adjustment method is to expand the distance between the centroids according to a preset coefficient; if the rules are still not met after the adjustment, the distance will continue to expand until it meets the rules. If the density is not in the set density interval, when it exceeds the lower limit of the interval, the distance between the centroids will be expanded by the preset coefficient; if the density exceeds the upper limit, the side length of the unit cell will be reduced by the given coefficient, and then iterate until the adjustment is made. The latter density enters the given density interval.

The automatic crystal generation module 24 sets the number of attempts according to needs, and the limit of the number of attempts is related to the running time and the amount of calculation acceptable to the user. The user can set any value between 0 and 1000000 as the number of attempts as needed. The number of attempts is set to prevent the system from entering an infinite loop mode because it fails to produce a crystal structure that conforms to the chemical plan and density interval. If a reasonable crystal structure has not been obtained after the limited number of times, the system will pause, and the user will be prompted to enter a reasonable crystal structure through the artificial crystal generation module, and then continue.

The invention generates crystals, that is, to generate virtual crystals, to determine the unit cell parameters in the CIF file describing the virtual crystals, the space group and the relative coordinate values of atoms in the molecules of each asymmetric unit in the unit cells. After entering the above parameters, the system will directly use the unit cell parameters in the parameters. There are 230 space groups in total, which are preset. The entire system works under the specified space group. The process of calculating the relative coordinate value of each atom in the unit cell from the input parameters is as follows: 1. For each molecule of asymmetric unit, randomly select an atom as the origin, and calculate according to the bond length and bond angle between the atoms in the molecule The coordinates of each atom relative to the origin. The rotatable flexible angle is determined according to the value in the input parameter. 2. Calculate the position of the center of mass of the molecule according to the coordinate position of each atom. That is, the weighted average of atomic mass and spatial position is used to determine the position of the center of mass. 3. Calculate the distance between two atoms, and take the vector between the two atoms with the longest distance as the orientation of the molecule. If the longest distance is more than one pair of atoms, take any one of them, and keep taking this pair of atoms every time to determine the orientation of the molecule. 4. Use 3-dimensional space transformation to transform the centroid and orientation of the molecule to the centroid coordinates and orientation given in the input parameters, so as to obtain the transformed coordinate value of each atom. The system uses this value directly for the relative coordinates of the atoms in the molecule in the unit cell. The virtual crystal construction is complete.

After receiving the crystal structure and adjusting the parameters, the unit cell parameters and the relative coordinates of each atom in the unit cell can be obtained from the crystal structure. Using the coordinates of each atom, the value of the intramolecular flexibility angle, the position of the center of mass of the molecule and the orientation of the vector between the two atoms with the longest intramolecular distance can be directly calculated. In this way, the aforementioned input parameters can be obtained.

As shown in FIG. 3 , the organic molecular crystal construction system 100 of the present invention further includes: a crystal evolution real-time monitoring module 90 : retrieves the generated crystal structure in real time, retrieves the crystal structure in the crystal database, and adjusts the crystal parameters during the crystal evolution process value. The crystal evolution real-time monitoring module 90 provides an interface to support the user to retrieve the crystal structure generated by the automatic crystal generation module in real time, and also supports the user to retrieve the crystal structure in the crystal database and the parameter adjustment values given by the crystal evolution module in real time. The interface returns crystal structure information in a CIF formatted file.

The artificial crystal generation module and the crystal evolution real-time monitoring module of the present invention provide a human-computer interaction interface for users to use.

The crystal energy calculation module 40 of this embodiment supports three kinds of precision crystal energy calculation methods, including:

The force field precision crystal energy calculation method module, this module supports the fast calculation of the energy of the crystal structure by the force field, input a crystal structure, the module will output the crystal structure and its corresponding crystal energy calculated by the force field. Commonly used force field calculation tools are Amber, charmm and so on.

Semi-empirical precision crystal energy calculation method module, the module supports the calculation of the energy of crystal structures with semi-empirical methods (such as DFTB). Input a crystal structure, and the module will output the crystal structure and its corresponding crystal energy calculated by the semi-empirical method. Semi-empirical calculation tools such as DFTB, Dmacrys

High-precision quantitative crystal energy calculation method module, the module supports the calculation of the energy of the crystal structure with high-precision quantitative methods (such as DFT). Input a crystal structure, the module will output the crystal structure and its corresponding crystal energy calculated by high-precision quantitative method. The calculation tools for high-precision quantization methods include VASP, Crystal09, etc.

The crystal evolution module 60 of this embodiment can optimize a given structure to obtain a crystal structure with better properties. The target of module optimization supports the following two.

The crystal energy is lower, and the particle swarm optimization algorithm and Monte Carlo search algorithm with the crystal energy as the optimization goal are supported to optimize the crystal structure. Enter the crystal energy calculated by a crystal structure and energy calculation module, and the module will output the adjusted value of the crystal structure parameters according to the algorithm rules. This output is passed into the automatic crystal generation module to generate new crystals.

The crystal structure density is larger, and the particle swarm optimization algorithm and Monte Carlo search algorithm with the crystal structure density as the optimization goal are supported to optimize the crystal structure. Enter the crystal energy calculated by a crystal structure and energy calculation module, and the module will output the adjusted value of the crystal structure parameters according to the algorithm rules. This output is passed into the automatic crystal generation module to generate new crystals.

The module stores the input crystal structure and its energy and output adjustments into the crystal database.

The evolution cycle iteration of the crystal is an iterative process according to the particle swarm optimization algorithm or the Monte Carlo optimization algorithm. The way that the crystal evolution module adjusts the structural parameters is according to the above optimization algorithm. For the initial crystal, since there is no historical information, according to the above optimization algorithm, each value of the crystal input parameters will be randomly fluctuated, so that a new crystal is obtained. The range of random fluctuations can be preset by the user in the system. The purpose of the adjustment is to obtain a new crystal structure, so that a crystal structure with good properties can be found. The use of particle swarm optimization algorithm and Monte Carlo optimization algorithm can better search in the optimization space, so that better crystal structures can be found more quickly.

The user can empirically set the number of iterations that will no longer produce lower-energy crystal structures. The process is as follows: the user sets the number of iterations, such as 1000; the system sets the initial minimum energy to 0, and records the number of iteration steps with the lowest energy to 0; each evolution iteration compares the energy of the current crystal structure with the lowest energy recorded by the system, If the current energy is lower, the lowest energy of the system is recorded as the current energy, and the number of iteration steps of the lowest energy is recorded as 0. If the current energy is high, add +1 to the minimum energy iteration steps. 4. If the minimum energy iteration steps exceed 1000, the system stops running.

In addition, the user can also set the number of iterations to judge that the crystal structure with lower density will no longer be produced according to experience. The process is as follows: 1. The user sets the number of iterations, such as 1000. 2. The system sets the initial minimum density as the upper limit of the density interval, and records the number of iteration steps for the minimum density as 0. 3. Each evolution iteration will compare the current crystal structure Density and the lowest density recorded by the system, if the current density is lower, record the lowest density of the system as the current density, and record the lowest density iteration steps as 0. If the current density is high, add +1 to the minimum density iteration steps. 4. If the minimum density iteration steps exceed 1000, the system stops running.

The crystal structure is stored and recalled by CIF file. After the system obtains the CIF file, it will obtain the input parameters according to the CIF file. Combining these input parameters into a one-dimensional vector in order satisfies the input of particle swarm optimization algorithm and Monte Carlo optimization algorithm.

After receiving the crystal structure and adjusting the parameters, the unit cell parameters and the relative coordinates of each atom in the unit cell can be obtained from the crystal structure. Using the coordinates of each atom, the value of the intramolecular flexibility angle, the position of the center of mass of the molecule and the orientation of the vector between the two atoms with the longest intramolecular distance can be directly calculated. In this way, the input parameters about the crystal can be obtained.

The crystal database 80 of this embodiment adopts a hybrid architecture of graph + file database. The core crystal data is stored directly in the file database in the CIF file format. The mutual evolution relationship between crystals is stored in a graph database. The crystal database supports the retrieval of crystal structure information according to the evolution relationship between crystals, and also supports fast retrieval of crystal structure information according to the creation time.

The core crystal data includes a CIF file for each crystal structure, as well as the tuning parameters for each. An evolution relationship is a record of how each crystal evolved from that crystal. The evolution information records a tree structure, and records the ID of its parent crystal for each crystal structure. If it is an initial crystal, the parent crystal ID is empty. The retrieval method is to enter a crystal structure ID, the system will search the crystal according to the ID, and get its father crystal ID, and then the system will search for the crystal according to the father crystal ID, and get the father crystal ID of this crystal, until the father crystal ID is empty. The system then returns a data set for these crystals. The entire evolutionary tree structure is the historical data of evolution.

The present invention adopts a framework design in which the model layer and the control layer are separated. The data storage of the model layer adopts the hybrid architecture of graph + file database, and the core crystal data is directly stored in the file database in CIF file format. The relationship between crystals is stored in a graph database. The control layer is developed in Python and includes a web service and a scheduling system for task distribution.

According to the organic molecular crystal construction system 100 of the present invention, a crystal structure with better properties can be obtained.

The user determines one or more initial crystal structure parameters based on their own experience or other tools. If the user does not have any experience and tools, the automatic crystal generation module can also be invoked to obtain one or more initial crystal structures.

The user invokes the interface of the artificial crystal generation module and inputs one or more crystal structure parameters obtained in the previous step. The module will construct the crystal structure and convert it into a crystal file in CIF format, and automatically transmit it to the crystal energy calculation module.

The crystal energy calculation module will call the corresponding algorithm module to calculate the energy of the crystal according to the energy precision preset by the user. The user can change the preset energy precision in advance through the interface. After the calculation is completed, the module will automatically transfer the crystal structure and calculated energy to the crystal evolution module.

If the crystal evolution module obtains the crystal structure for the first time during this run, the module will randomly adjust the crystal structure parameters, and store the crystal structure and adjusted values in the crystal database. If the crystal structure has been input to the crystal evolution module in the current operation of the system, the module will adjust the crystal structure parameters according to the preset particle swarm or Monte Carlo search algorithm. The user can preset the algorithm to be used through the interface. This module will automatically pass the crystal structure and tuning parameters into the automatic crystal generation module.

The automatic crystal generation module will automatically generate a new crystal structure, and then pass it into the crystal energy calculation module, and then into the crystal evolution module for loop iteration.

During the cycle, the user can retrieve the latest evolution structure information and evolution history data through the crystal evolution real-time monitoring module. The user can manually adjust the parameters of one or more of the crystal structures based on experience, and transfer the adjusted structure to the artificial crystal generation module. In this way, the cyclic process of crystal evolution continues from the artificially adjusted crystal. The whole system supports multiple evolution loops working simultaneously. The number of supported loops depends on the computational parallelism of the hardware device.

When the system continues to exceed the preset number of iterations and no new crystal structures with lower energy are produced, the system will automatically stop running.

The invention overcomes the defect that the existing crystal calculation and simulation method cannot effectively introduce artificial experience. On the basis of supporting the automatic evolution of crystals, it provides an interface for real-time evolution monitoring and manual modification, which allows users with rich professional experience to observe the process of crystal evolution and energy change in real time, and then adjust the evolution of the machine based on their own experience. route, which organically combines expert experience with the high efficiency of machine evolution. Thereby, a virtual crystal structure with better properties can be better obtained.

Taking the above ideal embodiments according to the present application as inspiration, and through the above descriptions, relevant personnel can make various changes and modifications without departing from the technical idea of the present application. The technical scope of the present application is not limited to the content in the description, and the technical scope must be determined according to the scope of the claims.

As will be appreciated by those skilled in the art, the embodiments of the present application may be provided as a method, a system, or a 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, etc.) 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 present application. It will be understood that each flow and/or block in the flowchart illustrations and/or block diagrams, and combinations of flows and/or blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer program instructions. These computer program instructions may be provided to the processor of a general purpose computer, special purpose computer, embedded processor or other programmable data processing device to produce a machine such that the instructions executed by the processor of the computer or other programmable data processing device produce Means for implementing the functions specified in a flow or flow of a flowchart and/or a block or blocks of a block diagram.

These computer program instructions may also be stored in a computer-readable memory capable of directing a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory result in an article of manufacture comprising instruction means, the instructions The apparatus implements the functions specified in the flow or flow of the flowcharts and/or the block or blocks of the block diagrams.

These computer program instructions can also be loaded on a computer or other programmable data processing device to cause a series of operational steps to be performed on the computer or other programmable device to produce a computer-implemented process such that The instructions provide steps for implementing the functions specified in the flow or blocks of the flowcharts and/or the block or blocks of the block diagrams.

Claims

A method for constructing organic molecular crystals, comprising:

Crystal generation: receive crystal parameters to generate crystals, generate crystal files according to the set format, form core crystal data, and store the core crystal data in the crystal database;

Crystal energy calculation: call the corresponding crystal energy calculation algorithm to calculate the crystal energy according to the crystal structure and the preset energy accuracy;

Crystal evolution: optimize based on crystal structure and calculated crystal energy, output crystal parameter adjustment values according to optimization algorithm rules, adjust crystal parameters and transfer to crystal generation step, generate new crystals, initial crystals and one or more optimized series of crystals The evolution relationship is formed, and the mutual evolution information between crystals is stored in the crystal database.
The method for constructing an organic molecular crystal according to claim 1, further comprising: real-time monitoring of crystal evolution: real-time retrieving the generated crystal structure, retrieving the crystal structure in the crystal database and adjusting the crystal parameters during the crystal evolution process The crystal parameters include: the molecular SMILES formula of each component of the crystal, the angle of each flexible angle of each molecule, the unit cell parameters, the position of the centroid of each molecule in the unit cell, the position of each molecule in the unit cell The crystal generation includes: artificial crystal generation: receiving crystal parameter input instructions or crystal parameter adjustment input instructions, and generating crystals according to the input parameters.
The method for constructing organic molecular crystals according to claim 1, wherein the crystal generation further comprises: automatic crystal generation: generating crystal parameters according to a specified target molecule or adjusting parameters according to parameter adjustment values of the crystal to generate a new crystal, Make a rationality judgment on the generation of new crystals. If the rationality judgment is passed, the crystal will be successfully generated. If the rationality judgment is not passed, the crystal parameters will be adjusted to regenerate the crystal.
The method for constructing an organic molecular crystal according to claim 3, wherein the rationality judgment comprises: judging whether the distance between two atoms in the crystal conforms to chemical rules, and judging whether the density of the crystal is within a given density range Inside.
The method for constructing organic molecular crystals according to claim 4, wherein the judging whether the chemical rules are met comprises: judging whether the distance and bond angle between any two atoms in the same molecule are equal to the difference between the two atoms in the molecule Determine whether the distance between two atoms of different molecules is not less than the van der Waals radius; the setting of the density interval includes: for each molecule of asymmetric unit, randomly select one The atom is the origin, the coordinates of each atom relative to the origin are calculated according to the bond length and bond angle between the atoms in the molecule, and the density d of the molecule in space is calculated by the mass of each atom and the position of each atom, with [a *d,b*d] Set the density interval of the crystal, where a, b are preset.
The method for constructing organic molecular crystals according to claim 4, wherein if the chemical rules are not met, the distance between the centroids of the molecules is adjusted, and the distance between the centroids is expanded by a preset coefficient. Continue to expand the distance between the centroids until they meet; if it is judged that the density of the crystal exceeds the lower limit of the density interval, expand the distance between the centroids according to the preset coefficient; if the density of the crystal exceeds the upper limit of the density interval, according to the set coefficient Reduce the side length of the unit cell, and iterate until the density of the crystal reaches the density range.
The method for constructing an organic molecule crystal according to any one of claims 1 to 6, wherein the unit cell parameters, the space group, and the relative coordinate values of the atoms in each asymmetric unit molecule in the unit cell are obtained, and the Work under the space group, calculate the relative coordinate value of each atom in the unit cell according to the input crystal parameters or adjust the input crystal parameters: for each molecule of asymmetric unit, randomly select an atom as the origin, Calculate the coordinates of each atom relative to the origin based on the bond length and bond angle between the Perform a weighted average with the spatial position to determine the position of the centroid, calculate the distance between two atoms, take the vector of the two atoms with the longest distance so far as the orientation of the molecule, and use the three-dimensional space transformation to transform the centroid and orientation of the molecule to the input crystal Parameters or adjust the coordinates and orientation of the center of mass given in the input crystal parameters, and obtain the transformed coordinate value of each atom as the relative coordinate value of the atoms in the molecule in the unit cell to generate a constructed crystal; or obtain it according to the crystal structure Unit cell parameters and the relative coordinates of each atom in the unit cell, according to the coordinates of each atom to calculate the intramolecular flexibility angle, the centroid text of the molecule and the vector orientation between the two atoms with the longest intramolecular distance, according to the crystal structure And adjust the input parameters to generate crystals.
The method for constructing an organic molecular crystal according to any one of claims 1 to 6, wherein the crystal database includes: a file database and a graph database, and the crystal data includes: a crystal file and each adjustment parameter, and the The crystal file includes: a CIF file, the crystal file is stored in a file database, the evolution information is recorded as a tree structure, the ID of its parent crystal is recorded for each crystal structure, and the parent crystal ID of the initial crystal is empty, so The evolution relationship is stored in the graph database, and the crystal evolution step includes: taking the crystal energy as the optimization target or the crystal structure density as the optimization target, using the particle swarm optimization algorithm or the Monte Carlo optimization algorithm to iteratively optimize the crystal structure, and obtain the crystal structure and Calculated crystal energy, according to particle swarm optimization algorithm or Monte Carlo optimization algorithm, output crystal parameter adjustment value, and transfer to the crystal generation step.
The method for constructing an organic molecular crystal according to claim 8, wherein, in the iterative optimization in the crystal evolution step, the initial minimum energy is 0, the number of falling steps for recording the minimum energy is 0, and the initial crystal is adjusted according to an optimization algorithm. Each parameter of the obtained crystal fluctuates randomly to obtain a new crystal, and iterates according to the preset number of iterations. If the crystal energy is the optimization goal, each evolution iteration compares the energy of the current crystal structure with the lowest recorded energy. If the current energy is lower, the lowest energy of the system is recorded as the current energy, and the number of iteration steps of the lowest energy is recorded as 0. If the current energy is high, the number of iteration steps of the lowest energy is +1, and if the number of iteration steps exceeds the preset number of iterations, it will stop. ;If the crystal density is the optimization goal, set the initial minimum density as the upper limit of the density interval, and record the minimum density iteration steps as 0. Each evolution iteration will compare the density of the current crystal structure with the recorded minimum density. If the current density is low, the lowest density of the system is recorded as the current density, and the number of iteration steps of the lowest density is recorded as 0. If the current density is high, the number of iteration steps of the lowest density is +1, and if the number of iteration steps exceeds the preset number of iterations, it will stop; The crystal energy calculation includes: a force field-accurate crystal energy calculation method based on the crystal structure and its corresponding force field to calculate the crystal energy, or a semi-empirical precision crystal energy calculation method based on the crystal structure and its corresponding semi-empirical method to calculate the crystal energy, or A high-precision quantitative crystal energy calculation method based on the crystal structure and its corresponding crystal energy calculated by a high-precision quantitative method.
A system for constructing organic molecular crystals, comprising:

Crystal generation module: receive crystal parameters to generate crystals, generate crystal files according to the set format, form core crystal data, and store the core crystal data in the crystal database;

Crystal energy calculation module: call the corresponding crystal energy calculation algorithm to calculate the crystal energy according to the crystal structure and the preset energy precision;

Crystal evolution module: optimize according to crystal structure and calculated crystal energy, output crystal parameter adjustment values according to optimization algorithm rules, adjust crystal parameters and transfer to crystal generation step, generate new crystal, initial crystal and a series of one or more optimizations The crystals form an evolution relationship, and the mutual evolution information between crystals is stored in the crystal database.