CN112086132A - Organic molecular crystal construction method and system - Google Patents
Organic molecular crystal construction method and system Download PDFInfo
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Abstract
A method and a system for constructing an organic molecular crystal comprise: receiving crystal parameters to generate crystals, generating a crystal file according to a set format to form core crystal data, and storing the core crystal data in a crystal database; calling a corresponding crystal energy calculation algorithm according to the crystal structure and the preset energy precision to calculate the crystal energy; optimizing according to the crystal structure and the calculated crystal energy, outputting a crystal parameter adjusting value according to an optimization algorithm rule, adjusting crystal parameters and transferring to a crystal generation step to generate new crystals, forming an evolution relation between the initial crystals and one or more optimized series of crystals, and storing the mutual evolution information between the crystals in a crystal database; the organic molecular crystal construction method and the system are optimized according to the crystal structure and the crystal energy through crystal evolution, crystal parameters are adjusted according to an optimization algorithm and are transferred to a crystal generation step for iteration, and the crystal structure with better properties is obtained through iterative optimization.
Description
Technical Field
The invention relates to a molecular crystal construction generation method, in particular to an organic molecular crystal construction method and system.
Background
The organic molecular crystal is widely applied to a plurality of fields such as medicines, daily chemical products, energetic materials and the like. How to rapidly design a crystal structure with better properties for given organic molecules directly determines the research and development speed and success rate of products. The traditional method relies on experimental large-scale screening to find different crystal structures through a large number of combinations of different experimental conditions and then select out those with better relative properties. In recent years, with the rapid increase in computing power, methods for simulating crystal structures and properties thereof by computation have been rapidly developed. The current calculation simulation method mainly depends on a global search and local optimization algorithm module to automatically generate and optimize a crystal structure, and the crystal structure with better property is screened out through the algorithm module.
The traditional experimental method cannot accurately design crystals on microscopic molecular scales, and can only find a crystal structure with better properties by combining a large number of experimental conditions and experimental methods according to macroscopic experimental experiences. The problem is that the overall process is relatively blind, since a large number of experimental conditions can be tried, and different combinations of solvents, temperatures, humidity, pressures, and changes in these factors over time can result in new crystal structures, as well as repeated crystal structures or no crystals. The efficiency of the overall process is relatively low and the selected crystal structure is only an optimal solution within the range found experimentally, and is likely not optimal if at all possible crystal structures.
Compared with the traditional experimental method, the current calculation simulation method is greatly improved. Because by computer virtual screening, billions of scale crystal structures can be stacked directly and then properties of these crystal structures calculated. This allows to find a crystal structure with better properties in a very large crystal space. However, it is difficult to find a crystal structure with better properties in such a large crystal space by using an algorithm alone, which puts a very high demand on the ability of the algorithm to search in the crystal space of a given molecule. Very high demands are also placed on the computational resources. Such computational simulation methods have performed well for relatively simple organic molecules. However, for the complex problem of more than 10 flex angles or more than 3 different molecules in the unit cell, the current computational simulation method performs poorly.
Disclosure of Invention
Based on this, there is a need for a method of constructing an organic molecular crystal that optimizes the resulting crystal structure.
Meanwhile, an organic molecular crystal construction system capable of optimizing the generated crystal structure is provided.
A method of constructing an organic molecular crystal, comprising:
crystal generation: receiving crystal parameters to generate crystals, generating a crystal file according to a set format to form core crystal data, and storing the core crystal data in a crystal database;
calculating the crystal energy: calling a corresponding crystal energy calculation algorithm according to the crystal structure and the preset energy precision to calculate the crystal energy;
crystal evolution: optimizing according to the crystal structure and the calculated crystal energy, outputting a crystal parameter adjusting value according to an optimization algorithm rule, adjusting crystal parameters and transferring to a crystal generation step to generate new crystals, forming an evolution relation between the initial crystals and the series of crystals optimized for one time or more times, and storing the mutual evolution information between the crystals in a crystal database.
In a preferred embodiment, further comprising: crystal evolution real-time monitoring: calling the generated crystal structure in real time, calling the crystal structure in a crystal database and adjusting values of crystal parameters in the crystal evolution process; the crystal parameters include: molecular SMILES formula for each component of the crystal, angle of each flexible angle of each molecule, unit cell parameters, centroid position of each molecule in the unit cell, orientation of each molecule in the unit cell; the crystal generation comprises: and (3) artificial crystal generation: and receiving a crystal parameter input instruction or a crystal parameter adjustment input instruction, and generating a crystal according to the input parameters.
In a preferred embodiment, the crystal growing further comprises: automatic crystal generation: generating crystal parameters according to the appointed target molecules or generating new crystals according to the parameter adjustment values of the crystals, judging the rationality of the generated new crystals, if the rationality is judged, successfully generating the crystals, and if the rationality is not judged, adjusting the crystal parameters to regenerate the crystals.
In a preferred embodiment, the rationality determination comprises: and judging whether the distance between every two atoms in the crystal accords with a chemical rule or not, and judging whether the density of the crystal is in a given density interval or not.
In a preferred embodiment, determining whether the chemical rule is met comprises: judging whether the distance and the bond angle between any two atoms in the same molecule are equal to the initial input or the adjustment input distance and the bond angle between the two atoms in the molecule, and judging whether the distance between the two atoms of different molecules is not less than the Van der Waals radius; the setting of the density interval comprises the following steps: randomly selecting an atom as an origin for each molecule of the asymmetric unit, calculating the coordinate of each atom relative to the origin according to the bond length and the bond angle between atoms in the molecule, calculating the density d of the molecule in space by using the mass of each atom and the position of each atom, and setting the density interval of crystals by [ a x d, b x d ], wherein a and b are preset.
In a preferred embodiment, if the chemical rules are not met, the centroid distance of the molecules is adjusted, the distance between centroids is expanded according to a preset coefficient, and if the chemical rules are not met after the adjustment, the distance between centroids is continuously expanded until the chemical rules are met; if the density of the crystal is judged to exceed the lower limit of the density interval, the distance between the centroids is enlarged according to a 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 according to a set coefficient, and iteration is carried out until the density of the crystal reaches the range of the density interval.
In a preferred embodiment, the cell parameters, space group, and relative coordinate values of atoms in each asymmetric unit molecule in the cell are obtained, the operation is performed under the designated space group, and the relative coordinate value of each atom in the cell is calculated according to the inputted crystal parameters or by adjusting the inputted crystal parameters: randomly selecting an atom as an origin for each molecule of the asymmetric unit, calculating the coordinate of each atom relative to the origin according to the bond length and the bond angle between atoms in the molecule, determining a rotatable flexible angle according to input crystal parameters or adjusting the input crystal parameters, calculating the centroid position of the molecule according to the coordinate position of each atom, performing weighted average on the mass and the space position of the atom to determine the position of the centroid, calculating the distance between every two atoms, taking the vector of the two atoms with the longest distance up to now as the orientation of the molecule, transforming the centroid and the orientation of the molecule to the input crystal parameters or adjusting the given centroid coordinate and the orientation in the input crystal parameters by using three-dimensional space transformation to obtain the transformed coordinate value of each atom as the relative coordinate value of the atom in the molecule in a unit cell to generate a constructed crystal; or obtaining the unit cell parameters and the relative coordinates of each atom in the unit cell according to the crystal structure, calculating the flexible angle in the molecule, the centroid character of the molecule and the vector orientation between the two atoms with the longest distance in the molecule according to the coordinates of each atom, and generating the crystal according to the crystal structure and the adjustment input parameters.
In a preferred embodiment, the crystal database comprises: a document database and a graph database, the crystal data comprising: a crystal file and adjustment parameters of each time, wherein the crystal file comprises: the CIF file, the crystal file is stored in the file database, the evolution information is recorded as a tree structure, the ID of the parent crystal of each crystal structure is recorded, the ID of the parent crystal of the initial crystal is empty, the evolution relation is stored in the graph database, and the crystal evolution step comprises the following steps: and (3) iteratively optimizing the crystal structure by using the crystal energy as an optimization target or the crystal structure density as an optimization target by adopting a particle swarm optimization algorithm or a Monte Carlo optimization algorithm to obtain the crystal structure and the calculated crystal energy, outputting a crystal parameter adjustment value according to the particle swarm optimization algorithm or the Monte Carlo optimization algorithm, and turning 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 of the recorded minimum energy is 0, the initial crystal randomly fluctuates each parameter of the obtained crystal according to an optimization algorithm to obtain a new crystal, iteration is performed according to a preset iteration number, if the crystal energy is taken as an optimization target, each evolution iteration compares the energy of the current crystal structure with the recorded minimum energy, if the current energy is lower, the system minimum energy is recorded as the current energy, the minimum energy iteration number is recorded as 0, if the current energy is high, the minimum energy iteration number is +1, and if the iteration number exceeds the preset iteration number, the iteration is stopped;
if the crystal density is taken as an optimization target, setting the initial minimum density as the upper limit of a density interval, recording the iteration step number of the minimum density as 0, comparing the density of the current crystal structure with the recorded minimum density in each evolution iteration, recording the system minimum density as the current density and recording the iteration step number of the minimum density as 0 if the current density is lower, and if the current density is high, performing iteration step number +1 on the minimum density, and stopping if the iteration step number exceeds the preset iteration number;
the crystal energy calculation includes: the crystal energy calculation method comprises a force field precision crystal energy calculation method for calculating crystal energy according to a crystal structure and a corresponding force field, a semi-empirical crystal energy calculation method for calculating crystal energy according to a crystal structure and a corresponding semi-empirical method, or a high-precision quantitative crystal energy calculation method for calculating crystal energy according to a crystal structure and a corresponding high-precision quantitative method.
An organic molecular crystal construction system comprising:
a crystal generation module: receiving crystal parameters to generate crystals, generating a crystal file according to a set format to form core crystal data, and storing the core crystal data in a crystal database;
a crystal energy calculation module: calling a corresponding crystal energy calculation algorithm according to the crystal structure and the preset energy precision to calculate the crystal energy;
a crystal evolution module: optimizing according to the crystal structure and the calculated crystal energy, outputting a crystal parameter adjusting value according to an optimization algorithm rule, adjusting crystal parameters and transferring to a crystal generation step to generate new crystals, forming an evolution relation between the initial crystals and the series of crystals optimized for one time or more times, and storing the mutual evolution information between the crystals in a crystal database.
The organic molecular crystal construction method and the system are optimized according to the crystal structure and the crystal energy through crystal evolution, crystal parameters are adjusted according to an optimization algorithm and are transferred to a crystal generation step for iteration, and the crystal structure with better properties is obtained through iterative optimization. And the evolution relation of the crystal is stored to track the evolution process of the crystal, and the crystal parameters can be modified according to the evolution process for optimization.
In addition, crystal structure is obtained for the first time during the operation of crystal evolution, crystal structure parameters can be randomly adjusted, and the crystal structure and the adjustment value are stored in a crystal database. If the crystal structure is input into the crystal evolution process in the system operation, the crystal structure parameters can 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. The module will automatically transmit the crystal structure and the adjustment parameters to the crystal generation step; the crystal generation step can automatically generate a new crystal structure, then the new crystal structure is transmitted into a crystal energy calculation process, and then the new crystal structure is transmitted into a crystal evolution process to carry out loop iteration. In the circulating process, a user can call newly evolved structure information and evolved historical data through the crystal evolution real-time monitoring module. The user may manually adjust parameters of one or more of the crystal structures empirically and pass the adjusted structure into the intraocular lens generation module. So that the cyclic process of crystal evolution continues to evolve from the artificially adjusted crystal. The whole system supports a plurality of evolution cycles to work simultaneously.
Drawings
FIG. 1 is a flow chart of a method for constructing an organic molecular crystal according to an embodiment of the present invention;
FIG. 2 is a block diagram of an organic molecular crystal building 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 fig. 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, generating a crystal file according to a set format to form core crystal data, and storing the core crystal data in a crystal database;
step S103, calculating crystal energy: calling a corresponding crystal energy calculation algorithm according to the crystal structure and the preset energy precision to calculate the crystal energy;
step S105, crystal evolution: optimizing according to the crystal structure and the calculated crystal energy, outputting a crystal parameter adjusting value according to an optimization algorithm rule, adjusting crystal parameters and transferring to a crystal generation step to generate new crystals, forming an evolution relation between the initial crystals and the series of crystals optimized for one time or more times, and storing the mutual evolution information between the crystals in a crystal database.
The method for constructing the organic molecular crystal further comprises the following steps: crystal evolution real-time monitoring: and calling the generated crystal structure in real time, calling the crystal structure in a crystal database and the crystal parameter adjustment value in the crystal evolution process.
The crystal parameters of the invention include: molecular SMILES formula for each component of the crystal, angle of each flexible angle of each molecule, unit cell parameters, centroid position of each molecule in the unit cell, orientation of each molecule in the unit cell;
the crystal generation step of the present invention comprises: artificial crystal generation and automatic crystal generation.
And (3) artificial crystal generation: and receiving a crystal parameter input instruction or a crystal parameter adjustment input instruction, and generating a crystal according to the input parameters.
The crystal parameters include: molecular SMILES of each component of the crystal, the angle (θ) per flexible angle per molecule11、θ12、…、θ1n），（θ21、θ22、…、θ2n），…，（θm1、θm2、…、θmn) Cell parameters (alpha, beta, gamma,a. b, c), centroid position (x) of each molecule in unit cell1、y1、z1），（x2、y2、z2），…，（xm、ym、zm) Orientation of each molecule in the unit cell (ω)1、ψ1、φ1），（ω2、ψ2、φ2），…，（ωm、ψm、φm). An interface may be provided to enable the user to directly import the parameters from which the module will directly generate the virtual crystal. Theta represents the flexibility angle in a molecule, i.e., the dihedral angle corresponding to a single rotatable bond in a molecule. Alpha, beta and gamma are included angles among 3 sides of the original point of the unit cell, and a, b and c are lengths of the 3 sides. Centroid position (x)m、ym、zm) Spatial coordinates representing the centroid of the mth molecule, orientation in the unit cell (ω)m、ψm、φm) And (3) representing the included angle between the vector formed by the two atoms with the farthest distance in the m-th molecule and 3 coordinate axes.
And modifying the parameters of the existing crystals in the crystal database to generate a new crystal structure. An interface may be provided for a user to read the structure in the crystal database, the user may directly modify one or more of the crystal parameters via the interface, and the module may generate a virtual crystal according to the new parameters.
Automatic crystal generation: generating crystal parameters according to the appointed target molecules or generating new crystals according to the parameter adjustment values of the crystals, judging the rationality of the generated new crystals, if the rationality is judged, successfully generating the crystals, and if the rationality is not judged, adjusting the crystal parameters to regenerate the crystals.
Specifically, the crystal structure is randomly generated, and for a specified target molecule, the module can automatically generate the crystal parameters and then make rationality judgment on the newly generated crystal. If the rationality judgment is passed, crystals are successfully generated, and if the rationality judgment is not passed, crystal parameters are adjusted to regenerate the crystals until a reasonable crystal structure is generated. The user may limit the number of attempts to reasonably crystal through the interface provided by the system.
And adjusting the given crystal structure to obtain a new crystal structure, receiving the crystal structure and the parameters needing to be adjusted by the module, and generating a new crystal by using the adjusted parameters. If the rationality judgment is passed, crystals are successfully generated, and if the rationality judgment is not passed, crystal parameters are adjusted to regenerate the crystals until a reasonable crystal structure is generated. The user may limit the number of attempts to reasonably crystal through the interface provided by the system.
Further, the rationality judgment of the present embodiment includes: and judging whether the distance between every two atoms in the crystal accords with a chemical rule or not, and judging whether the density of the crystal is in a given density interval or not.
Determining whether the chemical rule is satisfied comprises: judging whether the distance and the bond angle between any two atoms in the same molecule are equal to the initial input or the adjustment input distance and the bond angle between the two atoms in the molecule, and judging whether the distance between the two atoms of different molecules is not less than the Van der Waals radius; the setting of the density interval comprises the following steps: randomly selecting an atom as an origin for each molecule of the asymmetric unit, calculating the coordinate of each atom relative to the origin according to the bond length and the bond angle between atoms in the molecule, calculating the density d of the molecule in space by using the mass of each atom and the position of each atom, and setting the density interval of crystals by [ a x d, b x d ], wherein a and b are set in advance.
If the chemical rules are not met, adjusting the centroid distance of the molecules, expanding the distance between the centroids according to a preset coefficient, and if the chemical rules are not met after adjustment, continuing to expand the distance between the centroids until the centroids are met; if the density of the crystal is judged to exceed the lower limit of the density interval, the distance between the centroids is enlarged according to a 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 according to a set coefficient, and iteration is carried out until the density of the crystal reaches the range of the density interval.
The crystal generation needs to obtain the cell parameters, space group, and the relative coordinate value of the atom in each asymmetric unit molecule in the cell, work under the designated space group, and calculate the relative coordinate value of each atom in the cell according to the input crystal parameters or the adjustment of the input crystal parameters: randomly selecting an atom as an origin for each molecule of the asymmetric unit, calculating the coordinate of each atom relative to the origin according to the bond length and the bond angle between atoms in the molecule, determining a rotatable flexible angle according to input crystal parameters or adjusting the input crystal parameters, calculating the centroid position of the molecule according to the coordinate position of each atom, performing weighted average on the mass and the space position of the atom to determine the position of the centroid, calculating the distance between every two atoms, taking the vector of the two atoms with the longest distance up to now as the orientation of the molecule, transforming the centroid and the orientation of the molecule to the input crystal parameters or adjusting the given centroid coordinate and the orientation in the input crystal parameters by using three-dimensional space transformation to obtain the transformed coordinate value of each atom as the relative coordinate value of the atom in the molecule in a unit cell to generate a constructed crystal; or obtaining the unit cell parameters and the relative coordinates of each atom in the unit cell according to the crystal structure, calculating the flexible angle in the molecule, the centroid character of the molecule and the vector orientation between the two atoms with the longest distance in the molecule according to the coordinates of each atom, and generating the crystal according to the crystal structure and the adjustment input parameters.
The crystal database includes: a file database and a graph database. The crystal data include: crystal file and adjustment parameters for each time. The crystal file of the present embodiment includes: CIF files. The generation of crystals requires the determination of the unit cell parameters, space groups, and relative maximum coordinate values in the unit cell for atoms in the molecule of each asymmetric unit in the CIF file describing the crystal. After the parameters are input, the system will use the cell parameters directly, the space group is 230, the system works under the designated space group.
The crystal file of the present embodiment is stored in a file database. Evolution information is recorded as a tree structure, ID of the parent crystal of each crystal structure is recorded, and the ID of the parent crystal of the initial crystal is empty. The evolutionary relationships are stored in a graph database.
The crystal evolution step further comprises: and (3) iteratively optimizing the crystal structure by using the crystal energy as an optimization target or the crystal structure density as an optimization target by adopting a particle swarm optimization algorithm or a Monte Carlo optimization algorithm to obtain the crystal structure and the calculated crystal energy, outputting a crystal parameter adjustment value according to the particle swarm optimization algorithm or the Monte Carlo optimization algorithm, and turning to the crystal generation step.
And (3) iterative optimization in the crystal evolution step, wherein the initial minimum energy is 0, the falling step number of the minimum energy is recorded as 0, the initial crystal randomly fluctuates each parameter of the obtained crystal according to an optimization algorithm to obtain a new crystal, iteration is carried out according to preset iteration times, if the crystal energy is taken as an optimization target, each evolution iteration compares the energy of the current crystal structure with the recorded minimum energy, if the current energy is lower, the minimum energy of the system is recorded as the current energy, the minimum energy iteration step number is recorded as 0, if the current energy is high, the minimum energy iteration step number is +1, and if the iteration step number exceeds the preset iteration times, the system is stopped.
Further, the crystal energy calculation of the present embodiment includes: the crystal energy calculation method comprises a force field precision crystal energy calculation method for calculating crystal energy according to a crystal structure and a corresponding force field, a semi-empirical crystal energy calculation method for calculating crystal energy according to a crystal structure and a corresponding semi-empirical method, or a high-precision quantitative crystal energy calculation method for calculating crystal energy according to a crystal structure and a corresponding high-precision quantitative method.
The force field precision crystal energy calculation method supports the rapid calculation of the energy of the crystal structure by the force field. Inputting a crystal structure, and outputting the crystal structure and the corresponding crystal energy calculated by the force field by using the force field precision crystal energy calculation method. The calculation tools of the common force field precision crystal energy calculation method include Amber, charmm and the like,
a semi-empirical crystal energy calculation method supports the calculation of the energy of a crystal structure (such as DFTB) by a semi-empirical method. Inputting a crystal structure, the module will output the crystal structure and its corresponding crystal energy calculated by a semi-empirical method. The calculation tools of the semi-empirical precision crystal energy calculation method include DFTB and Dmac rys.
The high-precision quantification crystal energy calculation method supports calculating (such as DFT) the energy of the crystal structure with the high-precision quantification method. Inputting a crystal structure, and outputting the crystal structure and the corresponding crystal energy calculated by the high-precision quantification method by using the high-precision quantification crystal energy calculation method. The calculation tool for the Crystal energy calculation method with high accuracy is VASP, Crystal09, or the like.
As shown in fig. 2, an organic molecular crystal building system 100 according to an embodiment of the present invention includes:
the crystal generation module 20: receiving crystal parameters to generate crystals, generating crystal files according to a set format to form core crystal data, and storing the core crystal data in a crystal database 80;
crystal energy calculation module 40: calling a corresponding crystal energy calculation algorithm according to the crystal structure and the preset energy precision to calculate the crystal energy;
the crystal evolution module 60: optimizing according to the crystal structure and the calculated crystal energy, outputting crystal parameter adjustment values according to optimization algorithm rules, adjusting crystal parameters and transferring to a crystal generation step to generate new crystals, forming an evolution relation between the initial crystals and one or more optimized series of crystals, and storing the mutual evolution information between the crystals in a crystal database 80.
As shown in fig. 3, further, the crystal generating module 20 of the present embodiment includes: an intraocular lens generation module 22, and an automatic lens generation module 24.
The intraocular lens generation module 22 of the present embodiment. Two ways are provided for generating crystals. Inputting crystal parameters to directly construct the crystal. The crystal parameters include: molecular SMILES of each component of the crystal, the angle (θ) per flexible angle per molecule11、θ12、…、θ1n），（θ21、θ22、…、θ2n），…，（θm1、θm2、…、θmn) Unit cell parameters (α, β, γ, a, b, c), centroid position (x) of each molecule in the unit cell1、y1、z1），（x2、y2、z2），…，（xm、ym、zm) Each ofOrientation of individual molecules in the unit cell (ω)1、ψ1、φ1），（ω2、ψ2、φ2），…，（ωm、ψm、φm) The module provides an interface to support a user to directly input the parameters, and the module can directly generate the virtual crystal according to the parameters; and modifying the parameters of the existing crystals in the crystal database to generate a new crystal structure. The module provides an interface for a user to read structures in the crystal database, the user can directly modify one or more of the crystal parameters through the interface, and the module can generate a virtual crystal according to the new parameters. After the module generates the crystal, a crystal file is generated according to the standard format of the CIF for other modules of the system to use.
Smiles (simplified molecular input line entry specification), a specification for explicitly describing the structure of a molecule using ASCII character strings, simplifies the linear input of a molecule. SMILES describes a three-dimensional chemical structure with a string of characters, which necessarily transforms the chemical structure into a spanning tree, and employs a vertical-first traversal tree algorithm. During the conversion, hydrogen is removed and the ring is opened. When indicated, the atom at the end of the bond that is cleaved is indicated by a number and the branch is shown in parentheses. The SMILES string can be imported and converted by most molecular editing software into a two-dimensional graph or a three-dimensional model of a molecule. The conversion to two-dimensional graphics can be done using Helson's "Structure image Generation algorithms" (Structure Diagram Generation algorithms).
The automatic crystal generation module 24 of the present embodiment can automatically generate a crystal structure. The following two ways of generation are available. The crystal structure is randomly generated, and for a specified target molecule, the module can automatically generate the crystal parameters and then make rationality judgment on the newly generated crystal. If the rationality judgment is passed, crystals are successfully generated, and if the rationality judgment is not passed, crystal parameters are adjusted to regenerate the crystals until a reasonable crystal structure is generated. The user may limit the number of attempts to reasonably crystal through the interface provided by the system. 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 uses the adjusted parameters to generate a new crystal. If the rationality judgment is passed, crystals are successfully generated, and if the rationality judgment is not passed, crystal parameters are adjusted to regenerate the crystals until a reasonable crystal structure is generated. The user may limit the number of attempts to reasonably crystal through the interface provided by the system.
Criteria for rationality judgment are as follows:
the distance between every two atoms in the crystal needs to accord with the chemical rule;
the density of the crystals needs to be within a given density interval.
After the module generates the crystal, a crystal file is generated according to the standard format of the CIF for other modules of the system to use.
Chemical rules of rational judgment: 1. the distance and bond angle between two atoms within the same molecule are equal to the distance and bond angle of the initial input 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 the asymmetric unit, randomly selecting an atom as an origin, and calculating the coordinate of each atom relative to the origin according to the bond length and the bond angle between atoms in the molecule. Wherein the rotational compliance angle is determined from values in the input parameters; 2. calculating the density d of the molecule in space using the mass of each atom and the position of each atom; 3. and setting the density interval of the crystals by [ a, b, d ], wherein a, b can be preset according to the needs and experience of users.
The concrete process of judging the rationality is as follows: firstly, calculating standard values of the distance and the bond angle between atoms in the same molecule, the minimum value between two atoms between molecules and a density interval; for each generated virtual crystal structure, the distance between atoms in the same molecule, the bond angle, the distance between two atoms between molecules and the density are calculated. (ii) a Comparing with the first calculated value one by one, if the values are in accordance, the crystal is judged to be reasonable, and if one data is not in accordance, the crystal is judged to be unreasonable.
If the chemical rules do not meet, the centroid distance of the molecules is adjusted firstly, and the adjustment mode is to enlarge the distance between centroids according to a preset coefficient; and if the rule is not met after the adjustment, the distance is expanded continuously until the rule is met. If the density is not in the set density interval and exceeds the lower limit of the interval, expanding the distance between the centroids according to a preset coefficient; if the upper limit is exceeded, the cell side length is reduced by a given factor, and then iteration is performed until the adjusted density enters a given density interval.
The automatic crystal generation module 24 sets the number of attempts as needed, with limits on the number of attempts being related to the amount of run time and calculations that the user can accept. The user can set any value between 0 and 1000000 as the number of attempts as required. The number of attempts is set to prevent the system from entering a dead-cycle mode without producing a crystalline structure that fits within the chemical program and density ranges. If the reasonable crystal structure is not obtained for the limited times, the system is suspended, and the user is promoted to input a reasonable crystal structure through the artificial crystal generation module and then continues.
The invention generates crystal, namely virtual crystal, and determines the unit cell parameters, space group and relative coordinate value of atoms in the molecule of each asymmetric unit in the unit cell in CIF file describing the virtual crystal. After the parameters are input, the system directly uses the unit cell parameters in the parameters, the space group has a total of 230, the space group is preset, and the whole system works under the designated space group. The procedure for calculating the relative coordinate values of each atom in the unit cell from the input parameters is as follows: 1. for each molecule of the asymmetric unit, randomly selecting an atom as an origin, and calculating the coordinate of each atom relative to the origin according to the bond length and the bond angle between atoms in the molecule. Wherein the rotational compliance angle is determined from values in the input parameters. 2. The centroid position of the molecule is calculated from the coordinate position of each atom. Namely, the mass center position is determined by taking the atomic mass and the spatial position as weighted average. 3. And calculating the distance between every two atoms, and taking the vector between the two atoms with the longest distance as the orientation of the molecule. If the longest distance is not only one pair of atoms, one pair is taken arbitrarily, and the orientation of the molecule is determined by taking the pair of atoms each time after the holding. 4. And transforming the centroid and the orientation of the molecule into the centroid coordinates and the orientation given in the input parameters by using 3-dimensional space transformation, so as to obtain transformed coordinate values of each atom. The system uses this value directly for the relative coordinate values of the atoms in the molecule in the unit cell. The virtual crystal construction is completed.
Upon receiving the crystal structure and the tuning parameters, the cell parameters and the relative coordinates of each atom in the cell can be derived from the crystal structure. The coordinate of each atom can be used to directly calculate the value of the flexibility angle in the molecule, the centroid position of the molecule and the orientation of the vector between the two atoms with the longest distance in the molecule. The aforementioned input parameters are thus obtained.
As shown in fig. 3, the organic molecular crystal construction system 100 of the present invention further includes: crystal evolution real-time monitoring module 90: and calling the generated crystal structure in real time, calling the crystal structure in a crystal database and the crystal parameter adjustment value in the crystal evolution process. The crystal evolution real-time monitoring module 90 provides an interface to support a user to call the crystal structure generated by the automatic crystal generation module in real time, and also supports the user to call the crystal structure in the crystal database and the parameter adjustment value given by the crystal evolution module in real time. The interface returns crystal structure information in a file in CIF format.
The artificial crystal generation module and the crystal evolution real-time monitoring module provide a man-machine interaction interface for users to use.
The crystal energy calculation module 40 of the present embodiment supports three precision crystal energy calculation methods, including:
the module supports the energy of the crystal structure to be rapidly calculated by the force field, inputs a crystal structure, and outputs the crystal structure and the corresponding crystal energy calculated by the force field. Common force field calculation tools are Amber, charmm, etc.
A semi-empirical crystal energy calculation method module supports calculating the energy of a crystal structure (such as DFTB) using a semi-empirical method. Inputting a crystal structure, the module will output the crystal structure and its corresponding crystal energy calculated by a semi-empirical method. The semi-empirical calculation tools include DFTB and Dmac rys
And a high-precision quantification crystal energy calculation method module which supports the calculation (such as DFT) of the energy of the crystal structure by using a high-precision quantification method. A crystal structure is input, and the module outputs the crystal structure and the corresponding crystal energy calculated by a high-precision quantification method. The calculation tools of the high-precision quantization method include VASP, Crystal09 and the like.
The crystal evolution module 60 of this embodiment can optimize a given structure to obtain a crystal structure with better properties. The goal of module optimization supports the following two.
The crystal energy is lower, and the particle swarm algorithm and the Monte Carlo search algorithm which take the crystal energy as an optimization target are supported to optimize the crystal structure. The crystal structure and the crystal energy calculated by the energy calculation module are input, and the module outputs the value of crystal structure parameter adjustment according to the algorithm rule. The output is passed to an automatic crystal generation module to generate a new crystal.
The crystal structure density is larger, and the particle swarm algorithm and the Monte Carlo search algorithm which take the crystal structure density as an optimization target are supported to optimize the crystal structure. The crystal structure and the crystal energy calculated by the energy calculation module are input, and the module outputs the value of crystal structure parameter adjustment according to the algorithm rule. The output is passed to an automatic crystal generation module to generate a new crystal.
The module will store the input crystal structure and its energy and output adjustment values in a crystal database.
The evolution loop iteration of the crystal is an iteration process according to a particle swarm optimization algorithm or a Monte Carlo optimization algorithm. The mode of adjusting the structural parameters by the crystal evolution module is operated according to the optimization algorithm. For the initial crystal, since there is no historical information, each value of the crystal input parameters is randomly fluctuated according to the optimization algorithm, and thus a new crystal is obtained. The range of random fluctuations may 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. And the particle swarm optimization algorithm and the Monte Carlo optimization algorithm can be used for searching in the optimization space better, so that the crystal structure with better properties can be found more quickly.
The user can empirically set the number of iterations that will not produce a lower energy crystal structure. The process is as follows: the user sets the number of iterations, say 1000; the system sets the initial minimum energy as 0 and records the iteration step number of the minimum energy as 0; and comparing the energy of the current crystal structure with the lowest energy recorded by the system in each evolution iteration, and recording the lowest energy of the system as the current energy and recording the iteration step number of the lowest energy as 0 if the current energy is lower. If the current energy is high, the number of steps is iterated for the lowest energy + 1. 4. If the minimum energy iteration step number exceeds 1000, the system stops running.
Alternatively, the user may empirically set the number of iterations that no longer produce a lower density crystal structure. The process is as follows: 1. the user sets the number of iterations, say 1000. 2. The system sets the initial minimum density as the upper limit of the density interval and records the iteration step number of the minimum density as 0. And 3, comparing the density of the current crystal structure with the lowest density recorded by the system in each evolution iteration, and recording the lowest density of the system as the current density and recording the iteration step number of the lowest density as 0 if the current density is lower. If the current density is high, the number of steps is iterated for the lowest density + 1. 4. If the minimum density iteration step number exceeds 1000, the system stops running.
The crystal structure is stored and called by a CIF file, and the system can obtain input parameters according to the CIF file after acquiring the CIF file. The input parameters are combined into a one-dimensional vector in sequence, so that the input of a particle swarm optimization algorithm and a Monte Carlo optimization algorithm is met.
Upon receiving the crystal structure and the tuning parameters, the cell parameters and the relative coordinates of each atom in the cell can be derived from the crystal structure. The coordinate of each atom can be used to directly calculate the value of the flexibility angle in the molecule, the centroid position of the molecule and the orientation of the vector between the two atoms with the longest distance in the molecule. This allows to obtain input parameters for the crystal.
The crystal database 80 of the present embodiment employs a hybrid architecture of graph + file database. The crystal data of the core is directly stored in a file database in a CIF file format. And the mutual evolution relationship between the crystals is stored by a graph database. The crystal database supports retrieval of crystal structure information according to evolutionary relationships between crystals and also supports rapid retrieval of crystal structure information according to creation time.
The core crystal data includes CIF files for each crystal structure, and adjustment parameters for each time. The evolutionary relationship records each crystal as it evolves from that crystal. And recording a tree structure by evolution information, recording the ID of the parent crystal of each crystal structure, and if the crystal structure is the initial crystal, the ID of the parent crystal is empty. The searching method is to input a crystal structure ID, the system searches the crystal according to the ID and obtains the father crystal ID of the crystal, and then the system searches the crystal according to the father crystal ID and obtains the father crystal ID of the crystal until the father crystal ID is empty. The system then returns a data set of these crystals. The entire evolved tree structure is the evolved historical data.
The invention adopts the architecture design that the model layer and the control layer are separated. The data storage of the model layer adopts a mixed architecture of an image and a file database, and the crystal data of the core is directly stored in the file database in a CIF file format. And correlations between crystals are stored using a graph database. The control layer is developed with Python, and comprises a web service and a task distribution scheduling system.
The organic molecular crystal construction system 100 according to the present invention can obtain a crystal structure with better properties.
The user determines one or more initial crystal structure parameters based on his or her own experience or other tools. The automatic crystal generation module may also be invoked to obtain one or more initial crystal structures if the user does not have any experience or tools.
The user calls the interface of the artificial crystal generation module and transmits one or more crystal structure parameters obtained in the last step. The module constructs a crystal structure and converts the crystal structure into a crystal file in a CIF format, and the crystal file is automatically transmitted to the crystal energy calculation module.
The crystal energy calculating module calls a corresponding algorithm module to calculate the energy of the crystal according to the energy precision preset by the user. The user can previously change the preset energy precision through the interface. After the calculation is completed, the module will automatically transmit the crystal structure and the calculated energy to the crystal evolution module.
If the crystal evolution module obtains the crystal structure for the first time during the operation, the module randomly adjusts the crystal structure parameters and stores the crystal structure and the adjustment value into the crystal database. If a crystal structure is input into the crystal evolution module in the current operation of the system, the crystal structure parameters can be adjusted by the module according to a preset particle swarm or Monte Carlo search algorithm. The user can preset the algorithm to be used through the interface. The module will automatically pass the crystal structure and tuning parameters into the automatic crystal generation module.
The automatic crystal generation module automatically generates a new crystal structure, then transmits the new crystal structure into the crystal energy calculation module, and then transmits the new crystal structure into the crystal evolution module to carry out loop iteration.
In the circulating process, a user can call newly evolved structure information and evolved historical data through the crystal evolution real-time monitoring module. The user may manually adjust parameters of one or more of the crystal structures empirically and pass the adjusted structure into the intraocular lens generation module. So that the cyclic process of crystal evolution continues to evolve from the artificially adjusted crystal. The whole system supports a plurality of evolution cycles to work simultaneously. The number of support loops depends on the computational parallel capability of the hardware device.
When the system continues to exceed the preset number of iterations and no longer generates a new lower energy crystal structure, the system automatically stops running.
The invention overcomes the defect that the existing crystal calculation simulation method cannot effectively introduce artificial experience. On the basis of supporting automatic crystal evolution, an interface for real-time evolution monitoring and manual modification is provided, so that a user with abundant professional experience can observe the crystal evolution process and the energy change process in real time, and then the evolution route of the machine is adjusted by combining the experience of the user, so that the expert experience and the high efficiency of machine evolution can be organically combined together. Thereby better obtaining a virtual crystal structure with better properties.
In light of the foregoing description of the preferred embodiments according to the present application, it is to be understood that various changes and modifications may be made without departing from the spirit and scope of the invention. The technical scope of the present application is not limited to the contents of the specification, and must be determined according to the scope of the claims.
As will be appreciated by one skilled in the art, embodiments of the present application may be provided as a method, system, or computer program product. Accordingly, the present application may take the form of an entirely hardware embodiment, an entirely software embodiment or an embodiment combining software and hardware aspects. Furthermore, the present application may take the form of a computer program product embodied on one or more computer-usable storage media (including, but not limited to, disk storage, CD-ROM, optical storage, and the like) having computer-usable program code embodied therein.
The present application is described with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the application. It will be understood that each flow and/or block of the flow diagrams and/or block diagrams, and combinations of flows and/or blocks in the flow diagrams and/or block diagrams, can be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general purpose computer, special purpose computer, embedded processor, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions specified in the flowchart flow or flows and/or block diagram block or blocks.
These computer program instructions may also be stored in a computer-readable memory that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instruction means which implement the function specified in the flowchart flow or flows and/or block diagram block or blocks.
These computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide steps for implementing the functions specified in the flowchart flow or flows and/or block diagram block or blocks.
Claims (10)
1. A method for constructing an organic molecular crystal, comprising:
crystal generation: receiving crystal parameters to generate crystals, generating a crystal file according to a set format to form core crystal data, and storing the core crystal data in a crystal database;
calculating the crystal energy: calling a corresponding crystal energy calculation algorithm according to the crystal structure and the preset energy precision to calculate the crystal energy;
crystal evolution: optimizing according to the crystal structure and the calculated crystal energy, outputting a crystal parameter adjusting value according to an optimization algorithm rule, adjusting crystal parameters and transferring to a crystal generation step to generate new crystals, forming an evolution relation between the initial crystals and the series of crystals optimized for one time or more times, and storing the mutual evolution information between the crystals in a crystal database.
2. The method of claim 1, further comprising: crystal evolution real-time monitoring: calling the generated crystal structure in real time, calling the crystal structure in a crystal database and adjusting values of crystal parameters in the crystal evolution process; the crystal parameters include: molecular SMILES formula for each component of the crystal, angle of each flexible angle of each molecule, unit cell parameters, centroid position of each molecule in the unit cell, orientation of each molecule in the unit cell; the crystal generation comprises: and (3) artificial crystal generation: and receiving a crystal parameter input instruction or a crystal parameter adjustment input instruction, and generating a crystal according to the input parameters.
3. The method of claim 1, wherein the crystal growing further comprises: automatic crystal generation: generating crystal parameters according to the appointed target molecules or generating new crystals according to the parameter adjustment values of the crystals, judging the rationality of the generated new crystals, if the rationality is judged, successfully generating the crystals, and if the rationality is not judged, adjusting the crystal parameters to regenerate the crystals.
4. The method of constructing an organic molecular crystal according to claim 3, wherein the rationality judgment includes: and judging whether the distance between every two atoms in the crystal accords with a chemical rule or not, and judging whether the density of the crystal is in a given density interval or not.
5. The method of claim 4, wherein determining whether the chemical rules are met comprises: judging whether the distance and the bond angle between any two atoms in the same molecule are equal to the initial input or the adjustment input distance and the bond angle between the two atoms in the molecule, and judging whether the distance between the two atoms of different molecules is not less than the Van der Waals radius; the setting of the density interval comprises the following steps: randomly selecting an atom as an origin for each molecule of the asymmetric unit, calculating the coordinate of each atom relative to the origin according to the bond length and the bond angle between atoms in the molecule, calculating the density d of the molecule in space by using the mass of each atom and the position of each atom, and setting the density interval of crystals by [ a x d, b x d ], wherein a and b are preset.
6. The method of 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 enlarged by a preset coefficient, and if the rules are not met after the adjustment, the distance between the centroids is continuously enlarged until the centroids are met; if the density of the crystal is judged to exceed the lower limit of the density interval, the distance between the centroids is enlarged according to a 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 according to a set coefficient, and iteration is carried out until the density of the crystal reaches the range of the density interval.
7. The method according to any one of claims 1 to 6, wherein the cell parameters, space group, and relative coordinate values of atoms in each asymmetric unit molecule in the cell are obtained, the operation is performed under a specific space group, and the relative coordinate value of each atom in the cell is calculated according to the inputted crystal parameters or by adjusting the inputted crystal parameters: randomly selecting an atom as an origin for each molecule of the asymmetric unit, calculating the coordinate of each atom relative to the origin according to the bond length and the bond angle between atoms in the molecule, determining a rotatable flexible angle according to input crystal parameters or adjusting the input crystal parameters, calculating the centroid position of the molecule according to the coordinate position of each atom, performing weighted average on the mass and the space position of the atom to determine the position of the centroid, calculating the distance between every two atoms, taking the vector of the two atoms with the longest distance up to now as the orientation of the molecule, transforming the centroid and the orientation of the molecule to the input crystal parameters or adjusting the given centroid coordinate and the orientation in the input crystal parameters by using three-dimensional space transformation to obtain the transformed coordinate value of each atom as the relative coordinate value of the atom in the molecule in a unit cell to generate a constructed crystal; or obtaining the unit cell parameters and the relative coordinates of each atom in the unit cell according to the crystal structure, calculating the flexible angle in the molecule, the centroid character of the molecule and the vector orientation between the two atoms with the longest distance in the molecule according to the coordinates of each atom, and generating the crystal according to the crystal structure and the adjustment input parameters.
8. The method of constructing an organic molecular crystal according to any one of claims 1 to 6, wherein the crystal database includes: a document database and a graph database, the crystal data comprising: a crystal file and adjustment parameters of each time, wherein the crystal file comprises: the CIF file, the crystal file is stored in the file database, the evolution information is recorded as a tree structure, the ID of the parent crystal of each crystal structure is recorded, the ID of the parent crystal of the initial crystal is empty, the evolution relation is stored in the graph database, and the crystal evolution step comprises the following steps: and (3) iteratively optimizing the crystal structure by using the crystal energy as an optimization target or the crystal structure density as an optimization target by adopting a particle swarm optimization algorithm or a Monte Carlo optimization algorithm to obtain the crystal structure and the calculated crystal energy, outputting a crystal parameter adjustment value according to the particle swarm optimization algorithm or the Monte Carlo optimization algorithm, and turning to the crystal generation step.
9. The organic molecular crystal construction method according to claim 8, wherein in the crystal evolution step, iterative optimization is performed, the initial minimum energy is 0, the number of falling steps of the minimum energy is recorded as 0, the initial crystal randomly fluctuates each parameter of the obtained crystal according to an optimization algorithm to obtain a new crystal, iteration is performed according to a preset number of iterations, if crystal energy is taken as an optimization target, each evolution iteration compares the energy of the current crystal structure with the recorded minimum energy, if the current energy is lower, the system minimum energy is recorded as the current energy, the number of minimum energy iteration steps is recorded as 0, if the current energy is high, the number of minimum energy iteration steps is +1, and if the number of iteration steps exceeds the preset number of iterations, the iteration is stopped; if the crystal density is taken as an optimization target, setting the initial minimum density as the upper limit of a density interval, recording the iteration step number of the minimum density as 0, comparing the density of the current crystal structure with the recorded minimum density in each evolution iteration, recording the system minimum density as the current density and recording the iteration step number of the minimum density as 0 if the current density is lower, and if the current density is high, performing iteration step number +1 on the minimum density, and stopping if the iteration step number exceeds the preset iteration number; the crystal energy calculation includes: the crystal energy calculation method comprises a force field precision crystal energy calculation method for calculating crystal energy according to a crystal structure and a corresponding force field, a semi-empirical crystal energy calculation method for calculating crystal energy according to a crystal structure and a corresponding semi-empirical method, or a high-precision quantitative crystal energy calculation method for calculating crystal energy according to a crystal structure and a corresponding high-precision quantitative method.
10. An organic molecular crystal construction system, comprising:
a crystal generation module: receiving crystal parameters to generate crystals, generating a crystal file according to a set format to form core crystal data, and storing the core crystal data in a crystal database;
a crystal energy calculation module: calling a corresponding crystal energy calculation algorithm according to the crystal structure and the preset energy precision to calculate the crystal energy;
a crystal evolution module: optimizing according to the crystal structure and the calculated crystal energy, outputting a crystal parameter adjusting value according to an optimization algorithm rule, adjusting crystal parameters and transferring to a crystal generation step to generate new crystals, forming an evolution relation between the initial crystals and the series of crystals optimized for one time or more times, and storing the mutual evolution information between the crystals in a crystal database.
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