WO2023102870A1

WO2023102870A1 - Method and apparatus for computing free energy of molecule, and stability analysis method and apparatus, and device and storage medium

Info

Publication number: WO2023102870A1
Application number: PCT/CN2021/136976
Authority: WO
Inventors: 周天; 彭春望; 方利文; 孙广旭
Original assignee: 上海智药科技有限公司
Priority date: 2021-12-10
Filing date: 2021-12-10
Publication date: 2023-06-15

Abstract

The present application relates to a method and apparatus for computing the free energy of a molecule, and a stability analysis method and apparatus, and an electronic device and a storage medium. The method for computing the free energy of a molecule comprises: performing an energy minimization treatment on a molecule under test; under an isothermal-isobaric ensemble, when said molecule is in a balanced state at a preset temperature, computing the vibration frequency of said molecule in each coordinate direction; computing the potential energy and volume of said molecule; and on the basis of the vibration frequencies, and the potential energy and volume of said molecule, determining a curve of the free energy of said molecule changing, at the preset temperature, along with the volume. By means of the embodiments of the present application, for anisotropic molecular crystals having more atoms and flexible angles, the free energy of the molecular crystals can be accurately computed, thereby saving on the computing power and the computing time.

Description

Molecular free energy calculation, stability analysis method, device, equipment and storage medium

technical field

The present application relates to the technical field of molecular dynamics, in particular to a molecular free energy calculation and stability analysis method, device, equipment and storage medium.

Background technique

Crystal Structure Predict (CSP) is a very popular technology at present. The virtual crystal structure ranking displayed by CSP can only show the energy distribution of the crystal at 0K, while the experimental crystal structure screening is usually at room temperature. Therefore, it is necessary to calculate the relative free energy ranking among different crystal forms at room temperature.

In related technical solutions, some methods that can predict the absolute free energy of crystal molecules more accurately include calculation methods such as harmonic approximation method, quasi-harmonic approximation method, and pseudo-supercritical path method, but these methods generally have some problems. For example, for some organic molecular crystals with a large number of atoms, the cost of calculating the free energy by quantum chemical methods is high, or even impossible to calculate, and the packing mode of the crystal and the conformation of the molecules will hardly be changed during the calculation process. The research is unrealizable, and the simulated thermal expansion effect is isotropic, but for the usually anisotropic organic molecular crystals, the calculation results often have large errors.

technical problem

In the prior art methods for calculating the free energy of small drug molecules, the calculation cost is high or cannot be calculated, or the calculation results for the free energy of anisotropic organic molecules are inaccurate.

technical solution

The first aspect of the present application provides a molecular free energy calculation method, including:

Using a molecular dynamics method to perform energy minimization processing on the first crystal form of the molecule to be tested based on the force field data of the molecule to be tested, to obtain structural information of the first crystal form of the molecule to be tested after the energy minimization process;

Using a molecular dynamics method, based on the structural information of the first crystal form of the molecule to be tested after the energy minimization process, under the isothermal and isobaric ensemble, calculate the first crystal form of the molecule to be tested after the energy minimization process When the crystal form is in an equilibrium state at a preset temperature, the vibration frequency of all atoms in the first crystal form of the molecule to be tested in each coordinate direction, and the potential energy and volume of the first crystal form of the molecule to be tested;

Based on the vibration frequency, the potential energy and the volume of the first crystalline form of the analyte molecule, using a preset free energy calculation formula to determine the free energy of the first crystalline form of the analyte molecule at multiple preset temperatures Variation curve with volume;

The minimum free energy value in the free energy versus volume curve of the first crystal form of the molecule to be measured at each preset temperature is taken as the absolute free energy of the first crystal form of the molecule to be measured at the corresponding preset temperature. able.

As a possible implementation of the present application, in this implementation, the molecular dynamics method is used to minimize the energy of the first crystal form of the molecule to be tested based on the force field data of the molecule to be tested, to obtain The structural information of the first crystal form of the molecule to be tested after energy minimization processing, including:

Expanding the unit cell of the first crystalline form of the analyte molecule based on the force field data of the analyte molecule and the structure data of the first crystalline form of the analyte molecule to obtain a supercell of a preset size ;

Based on the force field data of the molecules to be tested, the energy minimization process is performed on the supercell to obtain the structural information of the supercell after the energy minimization process.

As a possible implementation of the present application, in this implementation, the molecular dynamics method is used, based on the structural information of the first crystal form of the molecule to be tested after the energy minimization process, under the isothermal and isobaric ensemble calculating the vibration frequencies of all atoms in the first crystal form of the molecule to be measured in each coordinate direction when the first crystal form of the molecule to be measured after energy minimization is in an equilibrium state at a preset temperature, and The potential energy and volume of the first crystal form of the molecule to be measured include:

In the preset temperature range, the isothermal and isobaric ensemble simulation is performed on the supercell after the energy minimization treatment, and the simulation trajectory of the supercell of the first crystal form of the molecule to be tested is obtained;

Select a plurality of temperature values in the preset temperature interval, and select simulation trajectory frames corresponding to the plurality of temperature values in the simulation trajectory of the supercell of the first crystal form of the molecule to be measured, respectively for multiple performing an isothermal and isobaric ensemble simulation on each of the simulated trajectory frames to obtain the volumes of the equilibrium states of the first crystal form of the molecule to be measured at the multiple temperature values;

Calculate the average value of the volume of the equilibrium state of the first crystal form of the molecule to be measured at the multiple temperature values, select a target simulation trajectory frame based on the average value, and select the target simulation trajectory frame corresponding to the target simulation trajectory frame. The supercell of the first crystal form of the measured molecule is subjected to energy minimization processing to obtain the molecular structure after energy minimization processing; wherein, the volume of the first crystal form of the molecule to be measured corresponding to the simulated trajectory frame is selected to be equal to the average volume The simulated trajectory frame with the smallest error is the target simulated trajectory frame;

Mode analysis is performed on the molecular structure after the energy minimization treatment, and the vibration frequencies of all atoms in the first crystal form of the molecule to be measured are calculated in each coordinate direction.

Using the steepest descent method and the conjugate gradient method in turn to perform energy minimization processing on the target simulation trajectory frame;

When the energy minimization process reaches the preset standard, calculate the potential energy and volume of the first crystal form of the molecule to be tested after the energy minimization process, and obtain the potential energy and volume of the first crystal form of the molecule to be tested volume.

As a possible implementation of the present application, in this implementation, the method further includes:

For any crystal form of the molecule to be tested, the method according to any one of claims 1-4 is used respectively to obtain the absolute free energy corresponding to the different crystal forms of the molecule to be tested at different preset temperatures.

The second aspect of the present application provides a molecular stability analysis method, the method comprising:

Using the method in the previous embodiment, obtain the absolute free energy of different crystal forms of the molecule to be tested at different preset temperatures;

Taking the absolute free energy of any crystal form at different preset temperatures as a reference, the absolute free energy of other crystal forms at the same preset temperature is subtracted from the reference to obtain the absolute free energy of each crystal form at different preset temperatures Relative free energy value;

Based on the relative free energy values of each crystal form at different preset temperatures, the most stable crystal form at a specific temperature is determined, and the crystal form corresponding to the lowest relative free energy value at the same temperature is the most stable crystal form.

The third aspect of the present application provides a molecular free energy calculation device, including:

The energy minimization module is used to perform energy minimization processing on the first crystal form of the molecule to be detected based on the force field data of the molecule to be detected by using a molecular dynamics method, so as to obtain the first crystal form of the molecule to be detected after energy minimization processing. - Structural information of the crystal form;

The balance simulation module is used to calculate the energy-minimized structure information of the first crystal form of the molecule to be tested by using molecular dynamics method under the isothermal and isobaric ensemble. When the first crystalline form of the analyte molecule is in equilibrium at a preset temperature, the vibration frequencies of all atoms in the first crystalline form of the analyte molecule in each coordinate direction, and the first crystalline form of the analyte molecule potential energy and volume;

The curve calculation module is used to determine the first crystal form of the molecule to be tested based on the vibration frequency, the potential energy and the volume of the first crystal form of the molecule to be tested by using a preset free energy calculation formula. Set the curve of free energy versus volume at temperature;

The free energy calculation module is used to use the minimum free energy value in the free energy versus volume curve of the first crystal form of the molecule to be measured at each preset temperature as the value of the molecule to be measured at the corresponding preset temperature Absolute free energy of the first crystal form.

The fourth aspect of the present application provides a molecular stability analysis device, the device comprising:

The absolute free energy calculation unit is used in the method in the foregoing embodiment to obtain the absolute free energy of different crystal forms of the molecule to be measured at different preset temperatures;

The relative free energy calculation unit is used to use the absolute free energy of any crystal form at different preset temperatures as a reference, and subtract the reference from the absolute free energy of other crystal forms at the same preset temperature to obtain each crystal The relative free energy value of the type at different preset temperatures;

The stable crystal form determination unit is used to determine the most stable crystal form at a specific temperature based on the relative free energy values of each crystal form at different preset temperatures, and the crystal form corresponding to the lowest relative free energy value at the same temperature is the most stable crystal form.

The fifth aspect of the present application provides an electronic device, including:

processor; and

A memory, on which executable codes are stored, which, when executed by the processor, cause the processor to perform the method as described above.

The sixth aspect of the present application provides a storage medium, on which executable code is stored, and when the executable code is executed by a processor of an electronic device, the processor is made to execute the above-mentioned method.

Beneficial effect

The technical solution provided by the application may include the following beneficial effects: the application obtains the force field data of the molecule to be tested, and performs energy minimization processing on the first crystal form of the molecule to be tested, and then calculates the When the first crystal form of the molecule to be measured is in an equilibrium state at a preset temperature, the vibration frequencies of all atoms in the first crystal form of the molecule to be measured in each coordinate direction, and the potential energy of the first crystal form of the molecule to be measured and volume, based on the vibration frequency, the potential energy and volume of the first crystalline form of the analyte molecule, using a preset free energy calculation formula to determine the first crystal form of the analyte molecule at multiple preset temperatures The change curve of free energy with volume can accurately calculate the free energy of molecular crystals for molecular crystals with more atoms, more flexible angles and anisotropy, saving computing power and computing time. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application.

Description of drawings

The above and other objects, features and advantages of the present application will become more apparent by describing the exemplary embodiments of the present application in more detail with reference to the accompanying drawings, wherein, in the exemplary embodiments of the present application, the same reference numerals generally represent same parts.

Fig. 1 is a schematic flow chart of a molecular free energy calculation method shown in the embodiment of the present application;

Fig. 2 is a schematic flow chart of a cell expansion method shown in the embodiment of the present application;

Fig. 3 is a schematic flow chart of a vibration frequency calculation method shown in an embodiment of the present application;

Fig. 4 is a schematic flow chart of a potential energy and volume calculation method shown in the embodiment of the present application;

5 is a schematic flow diagram of a molecular stability analysis method shown in the embodiment of the present application;

Fig. 6 is a schematic diagram of a molecular structure provided by an embodiment of the present application;

Fig. 7 is a diagram of the root mean square difference of molecular displacement as a function of time provided by the embodiment of the present application;

Figure 8 is a diagram of the change in molecular volume with time provided by the embodiment of the present application;

Fig. 9 is a schematic diagram of an absolute free energy curve provided in an embodiment of the present application;

Figure 10 is a graph of the relative free energy of different crystal forms as a function of temperature provided by the examples of the present application;

Fig. 11 is a kind of relative free energy curve chart that adopts PCSP calculation provided by the embodiment of the present application;

Fig. 12 is a schematic structural diagram of a molecular free energy calculation device provided in an embodiment of the present application;

Figure 13 is a schematic diagram of a molecular stability analysis device adopted in the embodiment of the present application;

FIG. 14 is a schematic structural diagram of an electronic device shown in an embodiment of the present application.

Embodiments of the present invention

Embodiments of the present application will be described in more detail below with reference to the accompanying drawings. Although embodiments of the present application are shown in the drawings, it should be understood that the present application may be embodied in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided so that this application will be thorough and complete, and will fully convey the scope of this application to those skilled in the art.

The terminology used in this application is for the purpose of describing particular embodiments only, and is not intended to limit the application. As used in this application and the appended claims, the singular forms "a", "the", and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. It should also be understood that the term "and/or" as used herein refers to and includes any and all possible combinations of one or more of the associated listed items.

It should be understood that although the terms "first", "second", "third" and so on may be used in this application to describe various information, such information should not be limited to these terms. These terms are only used to distinguish information of the same type from one another. For example, without departing from the scope of the present application, first information may also be called second information, and similarly, second information may also be called first information. Thus, a feature defined as "first" and "second" may explicitly or implicitly include one or more of these features. In the description of the present application, "plurality" means two or more, unless otherwise specifically defined.

In related technical solutions, some methods that can accurately predict the absolute free energy of crystal molecules include Harmonic Approximation (HA), Quasi Harmonic Approximation (QHA), pseudo-supercritical path (Pseudo-supercritical Path, PSCP) and other calculation methods, but these methods generally have some problems, such as for some organic molecular crystals with a large number of atoms, the cost of calculating free energy by quantum chemical methods is high, or even impossible to calculate, the calculation process The packing mode and molecular conformation of the crystal will hardly be changed, but the study of polymorphism is impossible, and the simulated thermal expansion effect is isotropic, while the calculation of the usually anisotropic organic molecular crystal The results are often very inaccurate.

In view of the above problems, the embodiment of the present application provides a molecular free energy calculation method, by obtaining the force field data of the molecule to be tested, and performing energy minimization on the first crystal form of the molecule to be tested, and then under the isothermal and isobaric ensemble , calculating the vibration frequencies of all atoms in the first crystal form of the molecule to be measured in each coordinate direction when the first crystal form of the molecule to be measured is in an equilibrium state at a preset temperature, and the first crystal form of the molecule to be measured The potential energy and volume of the type, based on the vibration frequency, the potential energy and volume of the first crystal form of the molecule to be measured, using the preset free energy calculation formula to determine the first crystal form of the molecule to be measured By setting the curve of free energy versus volume at temperature, the free energy of molecular crystals can be accurately calculated for molecular crystals with more atoms, more flexible angles, and anisotropy, saving computing power and computing time.

The technical solutions of the embodiments of the present application are described in detail below with reference to the accompanying drawings.

Fig. 1 is a schematic flowchart of a method for calculating free energy of a molecular crystal shown in an embodiment of the present application.

Referring to Figure 1, the molecular crystal free energy calculation method provided by the embodiment of the present application includes:

Step S101, using a molecular dynamics method to perform energy minimization on the first crystal form of the molecule to be tested based on the force field data of the molecule to be tested, to obtain the energy-minimized first crystal form of the molecule to be tested. structural information.

In the embodiment of this application, the molecular dynamics method is a molecular simulation method, and the pre-set gromacs (molecular dynamics program package) program can be used. The gromacs program is pre-set. First, the gromacs program is generated through the force field data The required input file, input the input file to the gromacs program, can perform functions such as energy minimization processing and equilibrium state simulation of any crystal form of the molecule to be tested; the molecule to be tested is a molecule that needs to calculate the free energy, and the molecule can have Multiple crystal forms, or only one crystal form; the free energy of the molecule in various crystal forms can be calculated by using the molecular free energy calculation method adopted in the embodiment of the present application. The force field data refers to the data used to represent the force field parameters between each atom in the molecule to be measured; the force field data can be stored in the form of a force field file for subsequent access. In the embodiment of the present application, it is also necessary to obtain the initial coordinate data of a certain crystal form of the molecule to be tested. The initial coordinate data refers to the coordinate data of the structure of the molecule to be tested in a certain crystal form placed in a three-dimensional rectangular coordinate system. The initial coordinate data is used to represent the coordinates of each atom in the molecule to be measured in a three-dimensional Cartesian coordinate system; the initial coordinate data can be stored in the form of a coordinate file, which is convenient for subsequent access. In the embodiments of the present application, the molecules to be measured are in different crystal type, the corresponding initial coordinate data are different.

In the embodiment of the present application, the energy minimization process refers to repeated iterative adjustment of the position of atoms in the first crystal form of the molecule to be tested to reduce the total energy of the crystal form system, wherein, in the energy minimization process, preset There is an iteration stop criterion, and when the iteration stop criterion is reached during the iteration, the iteration is stopped, the total energy of the crystal system is reduced to an expected critical point, and the energy-minimized first crystal form of the molecule to be tested is obtained. structural information.

Step S102, using the molecular dynamics method, based on the structural information of the first crystal form of the molecule to be tested after the energy minimization process, under the isothermal and isobaric ensemble, calculate the molecule to be tested after the energy minimization process When the first crystal form of the molecule is in equilibrium at a preset temperature, the vibration frequencies of all atoms in the first crystal form of the molecule to be measured in each coordinate direction, and the potential energy and volume.

In the embodiment of this application, the isothermal and isobaric ensemble (NPT ensemble) is an ensemble with controllable temperature and controllable pressure. In this ensemble, energy and volume can be exchanged between systems, but The sum of energy and volume of each system in the ensemble is constant, and in the embodiment of the present application, the molecule to be measured can be used as a system in the isothermal and isobaric ensemble.

As a possible implementation of the present application, in this embodiment, after the energy minimization process is performed on the molecules to be tested, the molecules to be tested are simulated under the isothermal and isobaric ensemble, and the specified temperature is selected in the preset temperature range , at the specified temperature, simulate the molecule to be measured to an equilibrium state, determine the structure of the molecule to be measured in the equilibrium state, and calculate the vibration frequency of the molecule to be measured in each coordinate direction under the structure. In the embodiment of the present application, the vibration frequency of the molecule to be measured in each coordinate direction refers to the vibration frequency of each atom in the molecule to be measured in the three directions of x-axis, y-axis and z-axis respectively.

In the embodiment of the present application, after the energy minimization process is performed on the first crystal form of the molecule to be tested, the potential energy and volume of the first crystal form of the molecule to be tested are calculated, wherein the potential energy refers to the first crystal form of the molecule to be tested The molecular potential energy in the state of energy minimization can be calculated by molecular dynamics methods, such as gromacs; similarly, the volume of the first crystal form of the molecule to be tested can also be calculated by molecular dynamics methods, such as gromacs.

Step S103, based on the vibration frequency, the potential energy and volume of the first crystalline form of the analyte molecule, using a preset free energy calculation formula to determine the first crystal form of the analyte molecule at multiple preset temperatures The curve of free energy as a function of volume.

In the embodiment of the present application, the calculated potential energy of the molecule to be measured is U, the volume is V, and the vibration frequency is ω, wherein the preset free energy formula can be as follows:

Among them, F(V,T) is the free energy of the molecule to be measured at the temperature T and volume V, U(V) is the potential energy of the molecule to be measured when the volume is V, N _A is Avogadro's constant, and P is the system Comprehensive pressure, k _B is the Boltzmann constant, k(ω) is the frequency of atom k,

To reduce Planck's constant, G(T) is expressed as the final free energy at temperature T.

In the embodiment of the present application, the above-mentioned formula can be used to solve the curve of the free energy of the molecule to be measured as a function of the volume at the temperature T.

Step S104, taking the minimum free energy value in the free energy versus volume curve of the first crystal form of the molecule to be tested at each preset temperature as the first crystal form of the molecule to be tested at the corresponding preset temperature of absolute free energy.

In the embodiment of the present application, according to the curve relationship between the free energy and the volume of the molecule to be measured at different temperatures, the minimum value of the free energy of the molecule to be measured at each temperature is selected, and these minimum values are the minimum values of the free energy of the molecule to be measured at the corresponding temperature. The absolute free energy at different temperatures can be obtained by using this method.

The technical solution provided by the present application may include the following beneficial effects: In the embodiment of the present application, by acquiring the force field data of the molecule to be tested and the initial coordinate data of the first crystal form of the molecule to be tested, and performing energy analysis on the first crystal form of the molecule to be tested Minimize the processing, and then under the isothermal and isobaric ensemble, calculate the vibration of all atoms in the first crystal form of the molecule to be measured in each coordinate direction when the first crystal form of the molecule to be measured is in an equilibrium state at a preset temperature frequency, and the potential energy and volume of the first crystal form of the molecule to be measured, based on the vibration frequency, the potential energy and volume of the first crystal form of the molecule to be measured, using a preset free energy calculation formula to determine the The curve of free energy versus volume of the first crystal form of molecules at multiple preset temperatures can accurately calculate the free energy of molecular crystals for molecular crystals with more atoms, more flexible angles and anisotropy. Save computing power and computing time.

As a possible implementation of the present application, in this implementation, as shown in Figure 2, the first crystal form of the molecule to be tested is analyzed based on the force field data of the molecule to be tested using a molecular dynamics method. Energy minimization processing, obtaining the structural information of the first crystal form of the molecule to be tested after energy minimization processing, including:

Step S201, based on the force field data of the molecule to be tested and the structure data of the first crystal form of the molecule to be tested, expand the unit cell of the first crystal form of the molecule to be tested to obtain a preset size supercell.

In the embodiment of the present application, the structural data of the molecule to be measured is a file storing a specific molecular structure, such as a .cif file or a .res file, and the cell in the structure file is expanded to generate a super Optionally, the preset size of the supercell is a 3×2×5 supercell. Optionally, the specific size of the supercell can be set according to needs, which is not limited here.

Step S202, based on the force field data of the molecule to be tested, perform energy minimization processing on the supercell, and obtain structural information of the supercell after energy minimization processing.

In the embodiment of the present application, the energy minimization process refers to repeated iterative adjustment of the position of atoms in the first crystal form of the molecule to be tested to reduce the total energy of the crystal form system, wherein, in the energy minimization process, preset There is an iteration stop criterion, when the iteration stop criterion is reached in the iteration, the iteration is stopped, the total energy of the crystal form system is reduced to an expected critical point, and the energy minimization treatment of the first crystal form of the molecule to be tested is obtained. Structural information of the supercell.

As a possible implementation of the present application, when the energy minimization process is performed on the first crystal form of the molecule to be tested, the pre-set gromacs program is used. The gromacs program is pre-set, and the gromacs program is first generated from the force field data The required input file, input the input file to the gromacs program to perform energy minimization on the supercell of the first crystal form of the molecule to be tested, and obtain the supercell of the first crystal form of the molecule to be tested after energy minimization structural information.

In the embodiment of the present application, the molecular structure is expanded and the energy minimization is performed on the expanded supercell to ensure the accuracy of the subsequent molecular free energy measurement.

As a possible implementation of the present application, in this implementation, as shown in Figure 3, molecular dynamics method is used, based on the structural information of the first crystal form of the molecule to be tested after the energy minimization process, in Under the isothermal and isobaric ensemble, when the first crystal form of the molecule to be tested after the energy minimization process is in an equilibrium state at a preset temperature, all atoms of the first crystal form of the molecule to be tested at each coordinate The vibration frequency of the direction, and the potential energy and volume of the first crystal form of the molecule to be measured include:

In step S301 , within a preset temperature range, an isothermal and isobaric ensemble simulation is performed on the energy-minimized supercell to obtain a simulated trajectory of the supercell of the first crystal form of the molecule to be tested.

In the embodiment of the present application, when calculating the vibration frequencies of all atoms in the first crystal form of the molecule to be tested, it is necessary to simulate the first crystal form of the molecule to be tested first. Simulation, following the previous example, after the energy minimization of the supercell, call the gromacs program to simulate the supercell after energy minimization, wherein the preset temperature range can be selected from a temperature range of 50K to 300K, and the temperature range It can be selected according to the actual situation, and this application does not make a limitation here. In this temperature range, NPT simulation is performed on the supercell. The preset step size can be selected as 1 fs, and the simulation time is 7 ns each time. The supercell is simulated with the above preset step size and simulation time, and the simulation result is obtained.

Step S302, selecting a plurality of temperature values in the preset temperature range, and selecting simulation trajectory frames respectively corresponding to the plurality of temperature values in the simulation trajectory of the supercell of the first crystal form of the molecule to be measured, performing isothermal and isobaric ensemble simulations on a plurality of the simulated trajectory frames respectively, to obtain volumes in equilibrium states of the first crystal form of the molecule to be measured at the plurality of temperature values respectively.

In the embodiment of the present application, the trajectory frame refers to the frame used to represent the coordinates and speed of each atom in the molecule at a certain moment or temperature point in the simulated trajectory. In the selected temperature range, multiple temperature values are selected, and in a specific implementation In the example, the selected temperature values are 50K, 60K, 70K, 80K, etc., and then the simulated trajectory frames corresponding to these temperature values can be obtained according to the preset step size, and then NPT simulation is performed on each simulated trajectory frame. Among them, Select the preset step size as 1fs, and each simulation time as 4ns, use the above preset step size and simulation time to simulate the supercell, and obtain the simulation results. When the molecules to be measured reach a stable equilibrium state, determine the molecules to be measured respectively The stable structure at each temperature value, and obtain the volume of the analyte molecule at each temperature value when it is stable.

Step S303, calculating the average value of the volumes of the equilibrium state of the first crystal form of the molecule to be measured at the multiple temperature values, selecting a target simulation trajectory frame based on the average value, and calculating the target simulation trajectory frame The supercell corresponding to the first crystal form of the molecule to be measured is subjected to energy minimization to obtain the molecular structure after the energy minimization process; wherein, the volume of the first crystal form of the molecule to be tested corresponding to the simulated trajectory frame is selected to match the The simulated trajectory frame with the smallest average volume error is the target simulated trajectory frame.

In the embodiment of the present application, the average volume of the molecule to be measured is calculated for the volume of the molecule to be measured when it is stable at each temperature value, and the target simulation trajectory frame is obtained, wherein the target molecule to be measured corresponding to the simulation trajectory frame The error between the volume of the molecule and the average volume is the smallest, and the average volume of the molecules to be measured can be accurately determined by using the average volume of the molecules to be measured. Simulation accuracy.

Step S304, performing mode analysis on the molecular structure after the energy minimization process, and calculating the vibration frequencies of all atoms in the first crystal form of the molecule to be measured in each coordinate direction.

In the embodiment of the present application, after the energy minimization process is performed on the molecule to be tested, the first crystal form of the molecule to be tested is simulated under the isothermal and isobaric ensemble, and a specified temperature is selected in a preset temperature range. Under the temperature, simulate the first crystal form of the molecule to be measured to an equilibrium state, determine the structure of the first crystal form of the molecule to be measured in the equilibrium state, and calculate all the first crystal forms of the molecule to be measured under the structure The vibration frequency of the atom in each coordinate direction. In the embodiments of the present application, the vibration frequencies of the molecules to be measured in each coordinate direction refer to the vibration frequencies of each atom of the first crystal form of the molecules to be measured in the three directions of x-axis, y-axis and z-axis respectively.

In the embodiment of the present application, by performing molecular dynamics sampling at different temperatures, an expansion volume with better anisotropy can be obtained, and problems such as isotropic expansion and high time consumption can be better dealt with.

As a possible implementation of the present application, in this implementation, as shown in Figure 4, molecular dynamics method is used, based on the structural information of the first crystal form of the molecule to be tested after the energy minimization process, in Under the isothermal and isobaric ensemble, when the first crystal form of the molecule to be tested after the energy minimization process is in an equilibrium state at a preset temperature, all atoms of the first crystal form of the molecule to be tested at each coordinate The vibration frequency of the direction, and the potential energy and volume of the first crystal form of the molecule to be measured include:

In step S401, the energy minimization process is performed on the target simulated trajectory frame by using the steepest descent method and the conjugate gradient method in sequence.

In the embodiment of this application, when performing energy minimization processing on the target simulation trajectory frame, the steepest descent method and the conjugate gradient method can be used in sequence, and the target simulation trajectory frame is used as input, and the steepest descent method and the conjugate gradient method are successively performed energy minimization.

Step S402, when the energy minimization process reaches the preset standard, calculate the potential energy and volume of the first crystalline form of the analyte molecule after the energy minimization process, and obtain the first crystalline form of the analyte molecule potential energy and volume.

In the embodiment of the present application, the molecular dynamics method is adopted. When the energy minimization reaches the preset standard, such as gradient ΔF<0.001, it means that the energy minimization reaches the minimum value, and the potential energy and volume of the molecule to be measured at this time are calculated.

For any crystal form of the molecule to be tested, the methods in the foregoing examples are used respectively to obtain the absolute free energy corresponding to different crystal forms of the molecule to be tested at different preset temperatures.

Step S402, select different preset temperatures, select the minimum value of free energy of the molecules to be measured, and obtain absolute free energy curves of the molecules to be measured at different preset temperatures.

In the embodiment of the present application, for the different crystal forms of the molecules to be tested, the molecular free energy calculation method provided in any of the foregoing embodiments can be used to calculate the absolute free energy curves of the crystal forms at different temperatures. The principle is the same as that of the foregoing The principles in the embodiments are similar and will not be repeated here.

In the embodiment of the present application, the molecular free energy calculation method provided can aim at the free energy when the molecule to be tested is in different crystal forms. After obtaining the initial coordinate data of different crystal forms of the molecule to be tested, the method provided in the previous examples can be used The free energy calculation method of molecules is used to calculate the free energy variation curves with volume at different preset temperatures for different crystal forms of the molecules to be tested. The calculation principle is the same as that of the previous embodiment, and will not be repeated here.

The technical solution provided by the present application may include the following beneficial effects: the embodiment of the present application obtains the force field data of the molecule to be tested and the initial coordinate data of different crystal forms of the molecule to be tested, and performs energy minimization for the different crystal forms of the molecule to be tested respectively. Then, under the isothermal and isobaric ensemble, respectively calculate the vibrations of all the atoms of the different crystal forms of the molecule to be tested in each coordinate direction when the different crystal forms of the molecule to be tested are in an equilibrium state at a preset temperature frequency, and the potential energy and volume of the different crystal forms of the molecule to be measured, and then based on the vibration frequencies of all atoms of the different crystal forms of the molecule to be measured in each coordinate direction, the potential energy of the different crystal forms of the molecule to be measured and volume, using the preset free energy calculation formula to determine the curves of the free energy versus volume of different crystal forms of the molecule to be tested at multiple preset temperatures. Anisotropic molecular crystals can accurately calculate the free energy of molecular crystals, saving computing power and computing time.

The embodiment of the present application provides a molecular stability analysis method, as shown in Figure 5, including:

Step S501, using the method in the foregoing embodiments, to obtain the absolute free energies of different crystal forms of the molecule to be measured at different preset temperatures.

In the embodiment of the present application, according to the foregoing embodiments, the absolute free energies of different crystal forms of the molecule to be tested at different temperatures can be determined, and the principle will not be repeated here.

Step S502, taking the absolute free energy of any one of the crystal forms at different preset temperatures as a reference, and subtracting the reference from the absolute free energy of other crystal forms at the same preset temperature, to obtain the absolute free energy of each crystal form at different preset temperatures. Relative free energy values at temperature.

In the examples of this application, for any crystal form of the molecule to be tested, the absolute free energy of the crystal form at different preset temperatures is used as a reference, and the absolute free energy of other crystal forms at the temperature is subtracted With this reference, the relative free energy of each crystal form at each temperature can be obtained.

Step S503, based on the relative free energy values of each crystal form at different preset temperatures, determine the most stable crystal form at a specific temperature, and the crystal form corresponding to the lowest relative free energy value at the same temperature is the most stable crystal form.

In the examples of the present application, for different crystal forms, at the same temperature, the crystal form with the lowest relative free energy is the most stable crystal form of the molecule to be tested at that temperature.

For the embodiment of the present application, for the convenience of description, take a specific embodiment as an example, as shown in Figure 6, which is the structural formula of the new crown drug Favipiravir (Favipiravir) molecule, and obtain the molecular coordinate file of the molecule. The file format can be It is a file in qbd format. Use the yoda program to capture the corresponding GAFF force field data, obtain a crystal structure cif file of a crystal form, expand the structure file to generate a 3x2x5 supercell, and read the force field data Generate the input file required by the gromacs (molecular dynamics method) program, call the gromacs program to minimize the energy of the supercell, and then call the gromacs program to perform NPT simulation on the energy-minimized supercell, and the temperature is raised from 50K to 300K , the step size is 1fs, the simulation is 7ns, and the simulation trajectory is obtained, and the trajectory frame of the time point corresponding to the specific temperature is extracted from the above simulation trajectory at an interval of 10K, and the NPT simulation is continued, the step size is 1fs, the simulation is 4ns, and finally all the temperatures are obtained The equilibrium structure below, its RMSD (Root Mean Square Difference of Displacement) and the variation of its volume with the simulation time are shown in Figures 7 and 8, respectively. The volume frame is used as input, and the energy minimization of the steepest descent method and the conjugate gradient method are carried out successively to ensure that the optimization reaches the convergence standard (such as gradient ΔF<0.001), and the potential energy (U) and the current volume (V) are calculated; call the gromacs program, Using the above energy-minimized structure as input, conduct mode analysis to calculate the vibration frequency (ω); use the following formula to calculate the curve of free energy versus volume at different temperatures.

According to the minimum value of the curve of free energy (F(V, T)) versus volume (V) at different temperatures (T), the absolute free energy ΔGabs(T) at the temperature can be obtained, as shown in Figure 9. Using the coordinate files of different crystal forms of the molecule to be measured as input and repeating the above steps, the relationship between the relative free energy of different crystal forms with temperature can be calculated, as shown in Figure 10. At the same time, for the same crystal form of the molecule, the relative free energy results calculated by PCSP are shown in Figure 11. The relative free energy trends of different structures in the low temperature segment are basically the same, but due to the limitations of the PSCP method itself, the 50K-90K The calculation result is inaccurate (not shown in this application), and the force field QHA and PSCP methods are calculated at the same time. The average core time ratio for each structure calculation is 663/2958, about 0.22. It shows that the molecular free energy calculation method provided in the examples of this application saves about 80% of the calculation cost while ensuring the correctness of the results.

Corresponding to the aforementioned embodiments of the method for realizing application functions, the present application also provides a molecular free energy calculation device, electronic equipment, and corresponding embodiments.

Fig. 12 is a schematic structural diagram of a molecular free energy calculation device shown in an embodiment of the present application.

Referring to Fig. 12, the molecular free energy calculation device 120 includes an energy minimization module 1210, a balance simulation module 1220, a curve calculation module 1230, and a free energy calculation module 1240, wherein:

The energy minimization module 1210 is configured to use a molecular dynamics method to perform energy minimization on the first crystal form of the molecule to be tested based on the force field data of the molecule to be tested, to obtain the energy minimization process of the molecule to be tested. Structural information of the first crystal form;

The balance simulation module 1220 is configured to use a molecular dynamics method, based on the structural information of the first crystal form of the molecule to be tested after the energy minimization process, to calculate the energy minimization process under the isothermal and isobaric ensemble. When the first crystalline form of the analyte molecule is in an equilibrium state at a preset temperature, the vibration frequencies of all atoms in the first crystalline form of the analyte molecule in each coordinate direction, and the first crystal form of the analyte molecule The potential energy and volume of the type;

The curve calculation module 1230 is configured to determine the first crystal form of the molecule to be measured in multiple The curve of free energy versus volume at a preset temperature;

The free energy calculation module 1240 is configured to use the minimum free energy value in the curve of free energy versus volume of the first crystal form of the molecule to be measured at each preset temperature as the value of the molecule to be measured at the corresponding preset temperature The absolute free energy of the first crystal form of .

As a possible implementation manner of the present application, in this embodiment, the energy minimization module 1210 performs energy minimization on the first crystal form of the molecule to be tested based on the force field data of the molecule to be tested by using a molecular dynamics method. When obtaining the structure information of the first crystal form of the molecule to be tested after energy minimization treatment, it can be used for:

As a possible implementation of the present application, in this embodiment, the equilibrium simulation module 1220 adopts the molecular dynamics method, based on the structural information of the first crystal form of the molecule to be tested after the energy minimization process, at an isothermal Under the isobaric ensemble, when the first crystal form of the molecule to be measured after the energy minimization process is in an equilibrium state at a preset temperature, all atoms of the first crystal form of the molecule to be measured in each coordinate direction The vibration frequency, and the potential energy and volume of the first crystal form of the molecule to be tested can be used for:

As a possible implementation of the present application, in this embodiment, the molecular free energy calculation device can also be used for:

For any crystal form of the molecule to be tested, the above method is used respectively to obtain the absolute free energy corresponding to the different crystal forms of the molecule to be tested at different preset temperatures.

Regarding the apparatus in the above embodiments, the specific manner in which each module executes operations has been described in detail in the embodiments related to the method, and will not be described in detail here.

The technical solution provided by the present application may include the following beneficial effects: In the embodiment of the present application, by acquiring the force field data of the molecule to be tested, and performing energy minimization on the first crystal form of the molecule to be tested, and then under the isothermal and isobaric ensemble, Calculating the vibration frequencies of all atoms in the first crystal form of the molecule to be measured in each coordinate direction when the first crystal form of the molecule to be measured is in equilibrium at a preset temperature, and the first crystal form of the molecule to be measured potential energy and volume, based on the vibration frequency, the potential energy and volume of the first crystal form of the molecule to be measured, using the preset free energy calculation formula to determine the first crystal form of the molecule to be measured in multiple preset The curve of free energy versus volume at temperature can accurately calculate the free energy of molecular crystals for molecular crystals with more atoms, more flexible angles, and anisotropy, saving computing power and computing time.

Fig. 13 is a schematic structural diagram of a molecular stability analysis device shown in an embodiment of the present application.

Referring to FIG. 13, the molecular stability analysis device 120 includes an absolute free energy calculation unit 1310, a relative free energy calculation unit 1320, and a stable crystal form determination unit 1330, wherein:

The absolute free energy calculation unit 1310 is used to obtain the absolute free energy of different crystal forms of the molecule to be measured at different preset temperatures by using the above method;

The relative free energy calculation unit 1320 is used to use the absolute free energy of any crystal form at different preset temperatures as a reference, and subtract the reference from the absolute free energy of other crystal forms at the same preset temperature to obtain each The relative free energy value of the crystal form at different preset temperatures;

The stable crystal form determining unit 1330 is used to determine the most stable crystal form at a specific temperature based on the relative free energy values of each crystal form at different preset temperatures, and the crystal form corresponding to the lowest relative free energy value at the same temperature is the most stable crystal form.

In the examples of the present application, the relative free energy of different crystal forms of the same molecule is generally calculated, and the crystal form with the lowest relative free energy at the same temperature is regarded as the most stable crystal form of the molecule at this temperature, so that the molecule can be accurately analyzed. steady state at different temperatures.

Referring to FIG. 14 , an electronic device 1000 includes a memory 1010 and a processor 1020 .

The processor 1020 can be a central processing unit (Central Processing Unit, CPU), and can also be other general-purpose processors, digital signal processors (Digital Signal Processor, DSP), application specific integrated circuits (Application Specific Integrated Circuit, ASIC), on-site Field-Programmable Gate Array (FPGA) or other programmable logic devices, discrete gate or transistor logic devices, discrete hardware components, etc. A general-purpose processor may be a microprocessor, or the processor may be any conventional processor, or the like.

The memory 1010 may include various types of storage units such as system memory, read only memory (ROM), and persistent storage. Wherein, the ROM may store static data or instructions required by the processor 1020 or other modules of the computer. The persistent storage device may be a readable and writable storage device. Persistent storage may be a non-volatile storage device that does not lose stored instructions and data even if the computer is powered off. In some embodiments, the permanent storage device adopts a mass storage device (such as a magnetic or optical disk, flash memory) as the permanent storage device. In some other implementations, the permanent storage device may be a removable storage device (such as a floppy disk, an optical drive). System memory can be a readable and writable storage device or a volatile readable and writable storage device, such as dynamic random access memory. System memory can store some or all of the instructions and data that the processor needs at runtime. In addition, the memory 1010 may include any combination of computer-readable storage media, including various types of semiconductor memory chips (such as DRAM, SRAM, SDRAM, flash memory, programmable read-only memory), and magnetic disks and/or optical disks may also be used. In some embodiments, memory 1010 may include a readable and/or writable removable storage device, such as a compact disc (CD), a read-only digital versatile disc (e.g., DVD-ROM, dual-layer DVD-ROM), Read-only Blu-ray Disc, Super Density Disc, Flash memory card (such as SD card, min SD card, Micro-SD card, etc.), magnetic floppy disk, etc. Computer-readable storage media do not contain carrier waves and transient electronic signals transmitted by wireless or wire.

Executable codes are stored in the memory 1010 , and when the executable codes are processed by the processor 1020 , the processor 1020 may execute part or all of the methods mentioned above.

In addition, the method according to the present application can also be implemented as a computer program or computer program product, the computer program or computer program product including computer program code instructions for executing some or all of the steps in the above method of the present application.

Alternatively, the present application may also be implemented as a computer-readable storage medium (or a non-transitory machine-readable storage medium or a machine-readable storage medium), on which executable code (or computer program or computer instruction code) is stored, When the executable code (or computer program or computer instruction code) is executed by the processor of the electronic device (or server, etc.), the processor is made to perform part or all of the steps of the above-mentioned method according to the present application.

Having described various embodiments of the present application above, the foregoing description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and alterations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principle of each embodiment, practical application or improvement of technology in the market, or to enable other ordinary skilled in the art to understand each embodiment disclosed herein.

Claims

A molecular free energy calculation method, characterized in that the method comprises: using a molecular dynamics method, based on the force field data of the molecule to be measured, performing energy minimization processing on the first crystal form of the molecule to be measured to obtain the energy Minimize the structural information of the first crystal form of the molecule to be measured after processing; using molecular dynamics methods, based on the structural information of the first crystal form of the molecule to be measured after the energy minimization process, in the isothermal and isobaric ensemble Next, calculate the vibration frequencies of all atoms in the first crystal form of the molecule to be tested in each coordinate direction when the first crystal form of the molecule to be tested after energy minimization treatment is in an equilibrium state at a preset temperature, and the potential energy and volume of the first crystal form of the molecule to be measured; based on the vibration frequency, the potential energy and volume of the first crystal form of the molecule to be measured, the preset free energy calculation formula is used to determine the The free energy of the first crystal form of the molecule varies with volume at a plurality of preset temperatures; The free energy value is taken as the absolute free energy of the first crystal form of the molecule to be measured at the corresponding preset temperature.
The molecular free energy calculation method according to claim 1, wherein the molecular dynamics method is used to minimize the energy of the first crystal form of the molecule to be measured based on the force field data of the molecule to be measured, Obtaining the structural information of the first crystal form of the molecule to be tested after the energy minimization process includes: based on the force field data of the molecule to be tested and the structure data of the first crystal form of the molecule to be tested, expand the unit cell of the first crystal form of the molecule to obtain a supercell with a preset size; based on the force field data of the molecule to be measured, perform energy minimization on the supercell to obtain the energy-minimized The structural information of the supercell.
The molecular free energy calculation method according to claim 2, wherein molecular dynamics is used, based on the structural information of the first crystal form of the molecule to be measured after the energy minimization process, in the isothermal and isobaric ensemble Next, calculate the vibration frequencies of all atoms in the first crystal form of the molecule to be tested in each coordinate direction when the first crystal form of the molecule to be tested after energy minimization treatment is in an equilibrium state at a preset temperature, and the potential energy and volume of the first crystal form of the molecule to be measured, including: performing isothermal and isobaric ensemble simulation on the supercell after energy minimization within a preset temperature range to obtain the first crystal form of the molecule to be measured. The simulated trajectory of the supercell of the crystal form; multiple temperature values are selected in the preset temperature range, and the simulated trajectory of the supercell of the first crystal form of the molecule to be measured is selected separately from the multiple temperature values For the corresponding simulated trajectory frame, perform isothermal and isobaric ensemble simulation on a plurality of the simulated trajectory frames respectively, to obtain the volumes of the equilibrium state of the first crystal form of the molecule to be measured at the multiple temperature values respectively; calculate The average value of the volumes of the equilibrium state of the first crystal form of the molecule to be measured at the multiple temperature values, based on the average value, the target simulation trajectory frame is selected, and the target simulation trajectory frame corresponding to the target The supercell of the first crystal form of the molecule is subjected to energy minimization processing to obtain the molecular structure after energy minimization processing; wherein, the error between the volume of the first crystal form of the molecule to be tested corresponding to the simulated trajectory frame and the average volume is selected The smallest simulated trajectory frame is the target simulated trajectory frame; performing mode analysis on the energy-minimized molecular structure, and calculating the vibration frequencies of all atoms in the first crystal form of the molecule to be measured in each coordinate direction.
The molecular free energy calculation method according to claim 3, characterized in that, using molecular dynamics method, based on the structural information of the first crystal form of the molecule to be measured after the energy minimization process, in the isothermal and isobaric ensemble Next, calculate the vibration frequencies of all atoms in the first crystal form of the molecule to be tested in each coordinate direction when the first crystal form of the molecule to be tested after energy minimization treatment is in an equilibrium state at a preset temperature, and the potential energy and volume of the first crystal form of the molecule to be measured, comprising: sequentially adopting the steepest descent method and the conjugate gradient method to perform energy minimization processing on the target simulation trajectory frame; when the energy minimization processing reaches the predetermined When setting a standard, calculate the potential energy and volume of the first crystal form of the molecule to be detected after the energy minimization process, and obtain the potential energy and volume of the first crystal form of the molecule to be detected.
The molecular free energy calculation method according to any one of claims 1 to 4, characterized in that the method further comprises: for any crystal form of the molecule to be tested, respectively adopting any of the crystal forms of claims 1-4 According to the method described above, the absolute free energy corresponding to the different crystal forms of the molecule to be tested is obtained at different preset temperatures.
A molecular stability analysis method, characterized in that, comprising: adopting the method according to claim 5 to obtain the absolute free energy of different crystal forms of the molecule to be measured at different preset temperatures; The absolute free energy at different preset temperatures is used as a reference, and the absolute free energy of other crystal forms at the same preset temperature is subtracted from the reference to obtain the relative free energy value of each crystal form at different preset temperatures; based on each The relative free energy values of crystal forms at different preset temperatures determine the most stable crystal form at a specific temperature.
The molecular stability analysis method according to claim 6, wherein the determination of the most stable crystal form at a specific temperature based on the relative free energy values of each crystal form at different preset temperatures includes:

The crystal form corresponding to the lowest relative free energy value at the same temperature was determined as the most stable crystal form.
A molecular free energy calculation device, characterized in that the device comprises:

The energy minimization module is used to perform energy minimization processing on the first crystal form of the molecule to be detected based on the force field data of the molecule to be detected by using a molecular dynamics method, so as to obtain the first crystal form of the molecule to be detected after energy minimization processing. - Structural information of the crystal form;

The balance simulation module is used to calculate the energy-minimized structure information of the first crystal form of the molecule to be tested by using molecular dynamics method under the isothermal and isobaric ensemble. When the first crystalline form of the analyte molecule is in equilibrium at a preset temperature, the vibration frequencies of all atoms in the first crystalline form of the analyte molecule in each coordinate direction, and the first crystalline form of the analyte molecule potential energy and volume;

The curve calculation module is used to determine the first crystal form of the molecule to be tested based on the vibration frequency, the potential energy and the volume of the first crystal form of the molecule to be tested by using a preset free energy calculation formula. Set the curve of free energy versus volume at temperature;

The free energy calculation module is used to use the minimum free energy value in the free energy versus volume curve of the first crystal form of the molecule to be measured at each preset temperature as the value of the molecule to be measured at the corresponding preset temperature Absolute free energy of the first crystal form.
The molecular free energy calculation device according to claim 7, wherein the energy minimization module performs molecular dynamics analysis on the first crystal form of the molecule to be tested based on the force field data of the molecule to be tested. Energy minimization processing, when obtaining the structural information of the first crystal form of the molecule to be tested after the energy minimization process, is used to: based on the force field data of the molecule to be tested and the first crystal form of the molecule to be tested Structural data, expanding the unit cell of the first crystal form of the molecule to be tested to obtain a supercell of a preset size; based on the force field data of the molecule to be tested, performing energy minimization processing on the supercell , to obtain the structural information of the supercell after energy minimization.
The molecular free energy calculation device according to claim 7, wherein the balance simulation module adopts a molecular dynamics method, based on the structural information of the first crystal form of the molecule to be measured after the energy minimization process, Under the isothermal and isobaric ensemble, when the first crystal form of the molecule to be measured after the energy minimization process is in an equilibrium state at a preset temperature, all the atoms of the first crystal form of the molecule to be measured are in each The vibration frequency in the coordinate direction, and the potential energy and volume of the first crystal form of the molecule to be measured are used for: performing an isothermal and isobaric ensemble simulation on the energy-minimized supercell within a preset temperature range , to obtain the simulated trajectory of the supercell of the first crystal form of the molecule to be measured; select a plurality of temperature values in the preset temperature range, and select from the simulated trajectory of the supercell of the first crystal form of the molecule to be measured The simulated trajectory frames corresponding to the plurality of temperature values respectively perform isothermal and isobaric ensemble simulation on the plurality of simulated trajectory frames to obtain the first crystal form of the molecule to be measured at the plurality of temperature values respectively The volume of the equilibrium state under the condition; calculate the average value of the volume of the equilibrium state of the first crystal form of the molecule to be measured at the multiple temperature values, and select the target simulation trajectory frame based on the average value, and the The supercell of the first crystal form of the molecule to be measured corresponding to the target simulation trajectory frame is subjected to energy minimization processing to obtain the molecular structure after energy minimization processing; wherein, the first crystal form of the molecule to be measured corresponding to the simulation trajectory frame is selected. The simulated trajectory frame with the smallest error between the volume and the average volume is the target simulated trajectory frame; the molecular structure after the energy minimization process is subjected to pattern analysis, and all atoms of the first crystal form of the molecule to be measured are calculated in each Vibration frequency in the coordinate direction.
The molecular free energy calculation device according to claim 7, wherein the balance simulation module adopts a molecular dynamics method, based on the structural information of the first crystal form of the molecule to be measured after the energy minimization process, Under the isothermal and isobaric ensemble, when the first crystal form of the molecule to be measured after the energy minimization process is in an equilibrium state at a preset temperature, all the atoms of the first crystal form of the molecule to be measured are in each The vibration frequency in the coordinate direction, and the potential energy and volume of the first crystal form of the molecule to be measured are used to: sequentially adopt the steepest descent method and the conjugate gradient method to perform energy minimization processing on the target simulation trajectory frame; when When the energy minimization process reaches the preset standard, calculate the potential energy and volume of the first crystal form of the molecule to be tested after the energy minimization process, to obtain the potential energy and volume of the first crystal form of the molecule to be tested .
The molecular free energy calculation device according to claim 7, characterized in that the device is also used to: adopt the method described in any one of claims 1-4 for any crystal form of the molecule to be measured, Obtain the absolute free energy corresponding to the different crystal forms of the molecule to be tested at different preset temperatures.
A molecular stability analysis device, characterized in that the device comprises:

The absolute free energy calculation unit is used to obtain the absolute free energy of different crystal forms of the molecule to be measured at different preset temperatures by using the method described in claim 5;

The relative free energy calculation unit is used to use the absolute free energy of any crystal form at different preset temperatures as a reference, and subtract the reference from the absolute free energy of other crystal forms at the same preset temperature to obtain each crystal The relative free energy value of the type at different preset temperatures;

The stable crystal form determination unit is used to determine the most stable crystal form at a specific temperature based on the relative free energy values of each crystal form at different preset temperatures, and the crystal form corresponding to the lowest relative free energy value at the same temperature is the most stable crystal form.
A device, characterized by comprising: a processor; and a memory on which executable codes are stored, and when the executable codes are executed by the processor, the processor is made to execute the method according to claims 1-6. any one of the methods described.
A storage medium, on which executable codes are stored, and when the executable codes are executed by a processor of an electronic device, the processor is made to execute the method according to any one of claims 1-6.