CN114187971B - Molecular free energy calculation and stability analysis method, device, equipment and storage medium - Google Patents
Molecular free energy calculation and stability analysis method, device, equipment and storage medium Download PDFInfo
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Abstract
The application relates to a molecular free energy calculation and stability analysis method and device, electronic equipment and a storage medium. The method comprises the following steps: performing energy minimization treatment on the molecules to be detected; under an isothermal and isobaric ensemble, when a molecule to be detected is in an equilibrium state at a preset temperature, calculating the vibration frequency of the molecule to be detected in each coordinate direction; calculating the potential energy and the volume of the molecule to be detected; and determining a change curve of the free energy of the molecule to be detected at the preset temperature along with the volume based on the vibration frequency, the potential energy and the volume of the molecule to be detected. According to the embodiment of the application, the free energy of the molecular crystal can be accurately calculated aiming at the anisotropic molecular crystal with more atomic numbers and more flexible angles, and the calculation force and the calculation time are saved.
Description
Technical Field
The present application relates to the field of molecular dynamics technologies, and in particular, to a method, an apparatus, a device, and a storage medium for calculating molecular free energy and analyzing stability.
Background
The prediction of small molecular Crystal form (CSP) is a very popular technology at present, and the virtual Crystal form ranking displayed by CSP can only show the energy distribution under 0K of Crystal, while the experimental Crystal form screening is usually performed at room temperature, so it is necessary to calculate the relative free energy ranking between different Crystal forms at room temperature.
In the related technical solutions, some methods that can accurately predict absolute free energy of crystal molecules include a simple harmonic approximation method, a quasi-simple harmonic approximation method, a pseudo supercritical path method, and other calculation methods, but these methods generally have problems, for example, for some organic molecular crystals with a large number of atoms, the cost for calculating free energy by a quantum chemical method is high, even calculation cannot be performed, the stacking mode of the crystals and the conformation of molecules are hardly changed in the calculation process, research on polymorphism is not realized, the simulated thermal expansion effect is isotropic, and the calculation result for the organic molecular crystals that are usually anisotropic often has a large error.
Disclosure of Invention
In order to solve or partially solve the problems in the related art, the application provides a molecular free energy calculation method, a molecular free energy calculation device, an electronic device and a storage medium, which can completely solve or partially solve the problems in the related technical scheme of molecular crystal form simulation research.
The first aspect of the present application provides a molecular free energy calculation method, including:
performing 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 adopting a molecular dynamics method to obtain the structural information of the first crystal form of the molecule to be detected after the energy minimization processing;
calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and the potential energy and the volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected subjected to the energy minimization treatment is in an equilibrium state at a preset temperature by adopting a molecular dynamics method based on the structural information of the first crystal form of the molecule to be detected subjected to the energy minimization treatment;
determining a change curve of the free energy of the first crystal form of the molecule to be detected along with the volume at a plurality of preset temperatures by adopting a preset free energy calculation formula based on the vibration frequency, the potential energy and the volume of the first crystal form of the molecule to be detected;
and taking the minimum free energy value in the change curve of the free energy of the first crystal form of the molecule to be detected along with the volume at each preset temperature as the absolute free energy of the first crystal form of the molecule to be detected at the corresponding preset temperature.
As a possible implementation manner of the present application, in this implementation manner, the performing, by using a molecular dynamics method, 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 to obtain the structural information of the first crystal form of the molecule to be detected after the energy minimization processing includes:
based on the force field data of the molecule to be detected and the structural data of the first crystal form of the molecule to be detected, carrying out cell expansion on the unit cell of the first crystal form of the molecule to be detected to obtain a supercell with a preset size;
and performing energy minimization on the supercell based on the force field data of the molecules to be detected to obtain the structural information of the supercell after the energy minimization.
As a possible embodiment of the present application, in this embodiment, a molecular dynamics method is used to calculate, based on the structural information of the first crystal form of the molecule to be detected after the energy minimization process, vibration frequencies of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and potential energy and volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected after the energy minimization process is in an equilibrium state at a preset temperature under an isothermal and isobaric ensemble, and includes:
carrying out isothermal isobaric ensemble simulation on the supercell subjected to energy minimization treatment in a preset temperature range to obtain a simulation track of the supercell of the first crystal form of the molecule to be detected;
selecting a plurality of temperature values in the preset temperature interval, selecting simulated track frames corresponding to the temperature values from simulated tracks of the supercell of the first crystal form of the molecule to be detected, and performing isothermal and isobaric ensemble simulation on the simulated track frames to obtain the volume of the first crystal form of the molecule to be detected in an equilibrium state under the temperature values;
calculating the average value of the volumes of the first crystal forms of the molecules to be detected in the equilibrium state under the temperature values respectively, selecting a target simulation track frame based on the average value, and performing energy minimization processing on the supercells of the first crystal forms of the molecules to be detected corresponding to the target simulation track frame to obtain the molecular structure after the energy minimization processing; selecting a simulation track frame corresponding to the simulation track frame and having the smallest error between the volume of the first crystal form of the molecule to be detected and the average value as a target simulation track frame;
and performing mode analysis on the molecular structure subjected to the energy minimization treatment, and calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction.
As a possible embodiment of the present application, in this embodiment, calculating, by using a molecular dynamics method, vibration frequencies of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and potential energy and volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected after the energy minimization treatment is in an equilibrium state at a preset temperature based on the structural information of the first crystal form of the molecule to be detected after the energy minimization treatment under an isothermal and isobaric system, includes:
sequentially adopting a steepest descent method and a conjugate gradient method to carry out energy minimization processing on the target simulation track frame;
and when the energy minimization treatment reaches a preset standard, calculating the potential energy and the volume of the first crystal form of the molecule to be detected after the energy minimization treatment is carried out, and obtaining the potential energy and the volume of the first crystal form of the molecule to be detected.
As a possible embodiment of the present application, in this embodiment, the method further includes:
and aiming at any crystal form of the molecule to be detected, respectively adopting the method of any one of claims 1 to 4 to obtain the corresponding absolute free energy of different crystal forms of the molecule to be detected at different preset temperatures.
In a second aspect, the present application provides a method for analyzing molecular stability, the method comprising:
obtaining absolute free energy of different crystal forms of the molecule to be detected at different preset temperatures by adopting the method in the previous embodiment;
taking the absolute free energy of any crystal form 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 relative free energy values of the crystal forms at different preset temperatures;
and determining the most stable crystal form at a specific temperature based on the relative free energy values of the crystal forms at different preset temperatures, and taking the crystal form corresponding to the lowest relative free energy value at the same temperature as the most stable crystal form.
A third aspect of the present application provides a molecular free energy calculation apparatus, including:
the energy minimization module is used for performing 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 adopting a molecular dynamics method to obtain the structural information of the first crystal form of the molecule to be detected after the energy minimization processing;
the balance simulation module is used for calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and the potential energy and the volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected after the energy minimization treatment is in a balance state at a preset temperature under an isothermal and isobaric ensemble by adopting a molecular dynamics method based on the structural information of the first crystal form of the molecule to be detected after the energy minimization treatment;
the curve calculation module is used for determining a free energy change curve of the first crystal form of the molecule to be detected along with the volume at a plurality of preset temperatures by adopting a preset free energy calculation formula based on the vibration frequency, the potential energy and the volume of the first crystal form of the molecule to be detected;
and the free energy calculation module is used for taking the minimum free energy value in the change curve of the free energy of the first crystal form of the molecule to be detected along with the volume at each preset temperature as the absolute free energy of the first crystal form of the molecule to be detected at the corresponding preset temperature.
The present application in a fourth aspect provides a molecular stability analysis device, comprising:
an absolute free energy calculation unit, configured to obtain absolute free energies of different crystal forms of the molecule to be detected at different preset temperatures, by using the method in the foregoing embodiment;
the relative free energy calculation unit is used for subtracting the reference from the absolute free energy of other crystal forms at the same preset temperature by taking the absolute free energy of any crystal form at different preset temperatures as the reference to obtain the relative free energy values of all crystal forms at different preset temperatures;
and the stable crystal form determining unit is used for determining the most stable crystal form at a specific temperature based on the relative free energy values of the crystal forms at different preset temperatures, and taking the crystal form which corresponds to the lowest relative free energy value at the same temperature as the most stable crystal form.
A fifth aspect of the present application provides an electronic device, comprising:
a processor; and
a memory having executable code stored thereon, which when executed by the processor, causes the processor to perform the method as described above.
A sixth aspect of the present application provides a storage medium having stored thereon executable code, which, when executed by a processor of an electronic device, causes the processor to perform the method as described above.
The technical scheme provided by the application can comprise the following beneficial effects: this application is through the force field data that acquires the molecule that awaits measuring to treat that the first crystal form of molecule that awaits measuring carries out energy minimizing process, then under isothermal isobaric ensemble, calculate the first crystal form of molecule that awaits measuring when predetermineeing the temperature and being in balanced state, all atoms of the first crystal form of molecule that awaits measuring are at the vibration frequency of each coordinate direction, and the potential energy and the volume of the first crystal form of molecule that awaits measuring, based on vibration frequency the potential energy and the volume of the first crystal form of molecule that awaits measuring adopt predetermined free energy computational formula to confirm the free energy of the first crystal form of molecule that awaits measuring is along with the change curve of volume under a plurality of temperature of predetermineeing is to the atomic number more, the more and anisotropic molecular crystal of flexible angle, can accurately calculate the free energy of molecular crystal, practices thrift calculated power and calculating 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.
Drawings
The foregoing and other objects, features and advantages of the application will be apparent from the following more particular descriptions of exemplary embodiments of the application as illustrated in the accompanying drawings wherein like reference numbers generally represent like parts throughout the exemplary embodiments of the application.
Fig. 1 is a schematic flow chart of a molecular free energy calculation method according to an embodiment of the present disclosure;
FIG. 2 is a schematic flow chart of a method for expanding cells according to an embodiment of the present disclosure;
FIG. 3 is a flow chart illustrating a method for calculating a vibration frequency according to an embodiment of the present disclosure;
FIG. 4 is a schematic flow chart diagram illustrating a potential energy and volume calculation method according to an embodiment of the present disclosure;
FIG. 5 is a schematic flow chart of a molecular stability analysis method according to an embodiment of the present disclosure;
FIG. 6 is a schematic diagram of a molecular structure provided in an embodiment of the present application;
FIG. 7 is a graph of RMS deviation of a molecular shift over time according to an embodiment of the present application;
FIG. 8 is a graph of molecular volume over time according to an embodiment of the present application;
FIG. 9 is a schematic diagram of an absolute free energy curve provided by an embodiment of the present application;
FIG. 10 is a graph of the relative free energy of a different crystalline form as a function of temperature as provided in the examples of the present application;
FIG. 11 is a graph of relative free energy using PCSP calculation according to an embodiment of the present disclosure;
FIG. 12 is a schematic structural diagram of a molecular free energy computing device according to an embodiment of the present application;
FIG. 13 is a schematic view of a molecular stability analysis apparatus through which embodiments of the present application may be passed;
fig. 14 is a schematic structural diagram of an electronic device according to an embodiment of the present application.
Detailed Description
Embodiments of the present application will be described in more detail below with reference to the accompanying drawings. While embodiments of the present application are illustrated in the accompanying drawings, it should be understood that the present application may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses 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," etc. may be used herein to describe various information, these information should not be limited to these terms. These terms are only used to distinguish one type of information from another. For example, first information may also be referred to as second information, and similarly, second information may also be referred to as first information, without departing from the scope of the present application. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present application, "a plurality" means two or more unless specifically limited otherwise.
In the related technical solutions, some methods capable of accurately predicting absolute free energy of crystal molecules include calculation methods such as a Harmonic Approximation (HA), a Quasi-Harmonic Approximation (QHA), a Pseudo-supercritical Path (PSCP), and the like, but these methods generally have problems, such as a high cost for calculating free energy by a quantum chemical method for some organic molecular crystals with a large atomic number, or even being unable to calculate free energy, a stacking mode of the crystals and a conformation of molecules are hardly changed in a calculation process, and research on polymorphism cannot be realized, and a simulated thermal expansion effect is isotropic, and a calculation result for organic molecular crystals which are usually anisotropic often HAs a large error.
In order to solve the above problems, an embodiment of the present application provides a molecular free energy calculation method, which includes acquiring force field data of a molecule to be measured, performing energy minimization processing on a first crystal form of the molecule to be measured, and then calculating vibration frequencies of all atoms of the first crystal form of the molecule to be measured in each coordinate direction and potential energy and volume of the first crystal form of the molecule to be measured when the first crystal form of the molecule to be measured is in an equilibrium state at a preset temperature under an isothermal and isobaric ensemble.
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 flow chart of a method for calculating free energy of a molecular crystal according to an embodiment of the present application.
Referring to fig. 1, a method for calculating a free energy of a molecular crystal provided in an embodiment of the present application includes:
step S101, performing 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 adopting a molecular dynamics method to obtain the structural information of the first crystal form of the molecule to be detected after the energy minimization processing.
In the embodiment of the application, the molecular dynamics method is a molecular simulation method, and a preset gromacs (molecular dynamics program package) program can be adopted, the gromacs program is preset, an input file required by the gromacs program is generated through force field data, the input file is input into the gromacs program, and functions of energy minimization processing, balance state simulation and the like can be performed on any crystal form of a molecule to be detected; the molecule to be detected is the molecule with free energy needing to be calculated, and the molecule can have various crystal forms or only one crystal form; the free energy of the molecule in various crystal forms can be calculated by adopting the molecular free energy calculation method in the embodiment of the application. The force field data are data used for expressing force field parameters among atoms in the molecules to be detected; the force field data can be stored in the form of a force field file, so that the force field data can be conveniently taken for subsequent use. In the embodiment of the present application, initial coordinate data of a certain crystal form of a molecule to be measured is also required to be obtained, where the initial coordinate data refers to coordinate data of a structure of the molecule to be measured in the certain crystal form placed in a three-dimensional rectangular coordinate system, and the initial coordinate data is used to represent coordinates of each atom in the molecule to be measured in the three-dimensional rectangular coordinate system; the initial coordinate data can be stored in a form of a coordinate file, so that the initial coordinate data can be conveniently taken for subsequent use in the embodiment of the application, and when the molecules to be detected are in different crystal forms, the corresponding initial coordinate data are different.
In the embodiment of the present application, the energy minimization process refers to repeatedly iteratively adjusting an atom position in the first crystal form of the molecule to be detected to reduce the total energy of the crystal form system, wherein an iteration stop standard is preset in the energy minimization process, and when the iteration stop standard is reached in the iteration, the iteration is stopped to reduce the total energy of the crystal form system to an expected critical point, and the structural information of the first crystal form of the molecule to be detected after the energy minimization process is obtained.
Step S102, calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and the potential energy and the volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected after the energy minimization treatment is in an equilibrium state at a preset temperature under an isothermal and isobaric ensemble by adopting a molecular dynamics method based on the structural information of the first crystal form of the molecule to be detected after the energy minimization treatment.
In the present embodiment, an isothermal isobaric ensemble (NPT ensemble) is an ensemble with controllable temperature and controllable pressure in which energy and volume exchange between systems is possible, but the sum of the energy and the sum of the volume of the systems within the ensemble are fixed, and in the present embodiment, the molecule under test can be used as one of the Wen Dengya ensembles.
As a possible embodiment of the present application, in the embodiment, after performing energy minimization processing on a molecule to be detected, the molecule to be detected is simulated under an isothermal and isobaric ensemble, a specified temperature is selected in a preset temperature interval, the molecule to be detected is simulated to an equilibrium state at the specified temperature, a structure of the molecule to be detected in the equilibrium state is determined, and vibration frequencies of the molecule to be detected in each coordinate direction under the structure are calculated. In the embodiment of the present application, the vibration frequency of the molecule to be detected in each coordinate direction refers to the vibration frequency of each atom in the molecule to be detected in three directions, namely, the x axis, the y axis and the z axis.
In the embodiment of the present application, after performing energy minimization processing on the first crystal form of the molecule to be detected, calculating potential energy and volume of the first crystal form of the molecule to be detected, where the potential energy refers to molecular potential energy of the first crystal form of the molecule to be detected in an energy minimization state, and may be obtained by calculation using a molecular dynamics method, such as gromacs; similarly, the volume of the first crystal form of the molecule to be detected can also be calculated by using a molecular dynamics method, such as gromacs.
And S103, determining a free energy change curve of the first crystal form of the molecule to be detected along with the volume at a plurality of preset temperatures by adopting a preset free energy calculation formula based on the vibration frequency, the potential energy and the volume of the first crystal form of the molecule to be detected.
In the embodiment of the present application, the potential energy of the molecule to be detected obtained through calculation is U, the volume is V, and the vibration frequency is ω, where the preset free energy formula may adopt the following formula:
wherein F (V, T) is free energy of the molecule to be detected at temperature T and volume V, U (V) is potential energy of the molecule to be detected at volume V, and N A Is the Avogastron constant, P is the ensemble pressure, k B Boltzmann constant, k (ω) is the frequency of the atom k,
to approximate the Planck constant, G (T) is expressed as the final free energy at temperature T.
In the embodiment of the present application, the curve of the free energy of the molecule to be measured changing with the volume at the temperature T can be solved by using the above formula.
And step S104, taking the minimum free energy value in the change curve of the free energy of the first crystal form of the molecule to be detected along with the volume at each preset temperature as the absolute free energy of the first crystal form of the molecule to be detected at the corresponding preset temperature.
In the embodiment of the application, the minimum value of the free energy of the molecule to be detected at each temperature is selected according to the curve relation between the free energy and the volume of the molecule to be detected at different temperatures, the minimum values are the absolute free energy of the molecule to be detected at the corresponding temperature, and the absolute free energy of the molecule to be detected at different temperatures can be obtained by adopting the method.
The technical scheme provided by the application can comprise the following beneficial effects: according to the embodiment of the application, through acquiring the force field data of the molecule to be detected and the initial coordinate data of the first crystal form of the molecule to be detected, performing energy minimization processing on the first crystal form of the molecule to be detected, and then calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and the potential energy and the volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected is in an equilibrium state at a preset temperature under an isothermal and isobaric system, based on the vibration frequency and the potential energy and the volume of the first crystal form of the molecule to be detected, the change curve of the free energy of the first crystal form of the molecule to be detected along with the volume is determined by adopting a preset free energy calculation formula, and the free energy of the molecule crystal can be accurately calculated aiming at the anisotropic molecule crystal with more atomic numbers and more flexible angles, so that the calculation force and the calculation time are saved.
As a possible embodiment of the present application, in this embodiment, as shown in fig. 2, the performing, by using a molecular dynamics method, 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 to obtain the structure information of the first crystal form of the molecule to be detected after the energy minimization processing, includes:
step S201, based on the force field data of the molecule to be detected and the structural data of the first crystal form of the molecule to be detected, the unit cell of the first crystal form of the molecule to be detected is expanded to obtain a supercell with a preset size.
In the embodiment of the present application, the structural data of the molecule to be detected is a file storing a specific molecular structure, for example, a cif file or a res file, and the unit cell in the structural file is subjected to cell expansion to generate a supercell with a preset size, optionally, the supercell with the preset size is a supercell with a size of 3 × 2 × 5, optionally, the specific size of the supercell may be set according to needs, and is not limited herein.
Step S202, based on the force field data of the molecules to be detected, the supercell is subjected to energy minimization processing, and the structural information of the supercell after the energy minimization processing is obtained.
In the embodiment of the present application, the energy minimization process refers to repeatedly iteratively adjusting an atomic position in the first crystal form of the molecule to be detected to reduce the total energy of the crystal form system, wherein an iteration stop standard is preset in the energy minimization process, and when the iteration stop standard is reached in the iteration, the iteration is stopped to reduce the total energy of the crystal form system to an expected critical point, and structural information of the supercell of the first crystal form of the molecule to be detected after the energy minimization process is obtained.
As a possible implementation manner of the present application, when performing energy minimization on the first crystal form of the molecule to be detected, a preset gromacs program is adopted, the gromacs program is preset, an input file required by the gromacs program is generated through force field data, the input file is input to the gromacs program to perform energy minimization on the supercell of the first crystal form of the molecule to be detected, and the structural information of the supercell of the first crystal form of the molecule to be detected after the energy minimization is performed can be obtained.
According to the embodiment of the application, the molecular structure is subjected to cell expansion, and the energy minimization treatment is performed on the supercell obtained by cell expansion, so that the accuracy of subsequent molecular free energy measurement is ensured.
As a possible embodiment of the present application, in this embodiment, as shown in fig. 3, when the energy-minimized first crystal form of the molecule to be measured is in an equilibrium state at a preset temperature under an isothermal and isobaric ensemble based on the structural information of the energy-minimized first crystal form of the molecule to be measured, the calculating of the vibration frequency of all atoms of the energy-minimized first crystal form of the molecule to be measured in each coordinate direction, and the potential energy and the volume of the energy-minimized first crystal form of the molecule to be measured by using a molecular dynamics method includes:
and S301, performing isothermal isobaric ensemble simulation on the supercell subjected to the energy minimization treatment in a preset temperature interval to obtain a simulation track of the supercell of the first crystal form of the molecule to be detected.
In this embodiment of the present application, when calculating the vibration frequencies of all atoms of the first crystal form of the molecule to be measured, the first crystal form of the molecule to be measured needs to be simulated first, optionally, the first crystal form of the molecule to be measured may be simulated under an isobaric isothermal system, and then, after energy minimization is performed on the supercell, a gromacs program is invoked to simulate the supercell after energy minimization, where a preset temperature range may be selected from a temperature range of 50K to 300K, and the temperature range may be selected according to an actual situation, which is not limited herein. And performing NPT simulation on the supercell in the temperature interval, wherein the preset step length can be selected to be 1fs, the simulation time is 7ns each time, and the supercell is simulated by adopting the preset step length and the simulation time to obtain a simulation result.
Step S302, selecting a plurality of temperature values in the preset temperature interval, selecting simulation track frames corresponding to the temperature values from simulation tracks of the supercell of the first crystal form of the molecule to be detected, and performing isothermal and isobaric ensemble simulation on the simulation track frames respectively to obtain the volume of the first crystal form of the molecule to be detected in an equilibrium state under the temperature values respectively.
In the embodiment of the application, a track frame refers to a frame in which a certain time or temperature point in a simulated track is used for representing coordinates and speeds of atoms in molecules, a plurality of temperature values are selected in a selected temperature interval, in a specific embodiment, the selected temperature values are 50K, 60K, 70K, 80K and the like, then simulated track frames corresponding to the temperature values can be obtained respectively according to preset step lengths, then NPT simulation is performed on each simulated track frame, wherein the preset step length can be selected to be 1fs, the simulation time is 4ns each time, the supercell is simulated by adopting the preset step length and the simulation time to obtain a simulation result, when the molecules to be detected reach a stable equilibrium state, the stable structures of the molecules to be detected under each temperature value are determined, and the volumes of the molecules to be detected under each temperature value are obtained.
Step S303, calculating an average value of the volumes of the first crystal forms of the molecules to be detected in the equilibrium state under the temperature values respectively, selecting a target simulation track frame based on the average value, and performing energy minimization processing on the supercells of the first crystal forms of the molecules to be detected corresponding to the target simulation track frame to obtain a molecular structure after the energy minimization processing; and selecting the simulation track frame with the minimum error between the volume of the first crystal form of the molecule to be detected corresponding to the simulation track frame and the average value as a target simulation track frame.
In this application embodiment, to the volume of the molecule that awaits measuring when every temperature value is stable, calculate the average volume of the molecule that awaits measuring to obtain target simulation orbit frame, wherein, the volume of the molecule that awaits measuring that target simulation orbit frame corresponds with the error of average volume is minimum, adopts the average volume of the molecule that awaits measuring can be accurate confirm the average level of the molecule that awaits measuring under different temperatures, then confirms target simulation orbit frame based on the average level of the molecule volume that awaits measuring, guarantees the accuracy of simulation.
Step S304, performing mode analysis on the molecular structure subjected to the energy minimization treatment, and calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction.
In the embodiment of the application, after energy minimization processing is performed on a molecule to be detected, a first crystal form of the molecule to be detected is simulated under an isothermal and isobaric ensemble, a specified temperature is selected in a preset temperature range, the first crystal form of the molecule to be detected is simulated to be in an equilibrium state at the specified temperature, a structure of the first crystal form of the molecule to be detected in the equilibrium state is determined, and vibration frequencies of all atoms of the first crystal form of the molecule to be detected in all coordinate directions under the structure are calculated. In the embodiment of the present application, the vibration frequency of the molecule to be detected in each coordinate direction refers to the vibration frequency of each atom of the first crystal form of the molecule to be detected in three directions, namely, the x axis, the y axis and the z axis.
In the embodiment of the application, by performing molecular dynamics sampling at different temperatures, the expansion volume with better anisotropy can be obtained, and the problems of isotropic expansion, high time consumption and the like can be better solved.
As a possible embodiment of the present application, in this embodiment, as shown in fig. 4, when the energy-minimized first crystal form of the molecule to be measured is in an equilibrium state at a preset temperature under an isothermal and isobaric ensemble based on the structural information of the energy-minimized first crystal form of the molecule to be measured, the calculating of the vibration frequency of all atoms of the energy-minimized first crystal form of the molecule to be measured in each coordinate direction, and the potential energy and the volume of the energy-minimized first crystal form of the molecule to be measured by using a molecular dynamics method includes:
and S401, sequentially adopting a steepest descent method and a conjugate gradient method to perform energy minimization processing on the target simulation track frame.
In this embodiment of the present application, when performing energy minimization processing on a target simulation track frame, a steepest descent method and a conjugate gradient method may be sequentially adopted, and the target simulation track frame is used as an input, and energy minimization is performed by the steepest descent method and the conjugate gradient method sequentially.
Step S402, when the energy minimization reaches a preset standard, calculating the potential energy and the volume of the first crystal form of the molecule to be detected after the energy minimization to obtain the potential energy and the volume of the first crystal form of the molecule to be detected.
In the embodiment of the present application, a molecular dynamics method is used, when the energy minimization reaches a preset standard, for example, the gradient Δ F <0.001, it indicates that the energy minimization reaches a minimum value, and the potential energy and the volume of the molecule to be measured at this time are calculated.
As a possible embodiment of the present application, in this embodiment, the method further includes:
and aiming at any crystal form of the molecule to be detected, obtaining the absolute free energy corresponding to different crystal forms of the molecule to be detected at different preset temperatures by respectively adopting the method in the embodiment.
And S402, selecting the minimum value of the free energy of the molecule to be detected at different preset temperatures to obtain absolute free energy curves of the molecule to be detected at different preset temperatures.
In the embodiment of the present application, for different crystal forms of a molecule to be detected, the absolute free energy curve of the crystal form at different temperatures may be calculated by using the molecular free energy calculation method provided in any embodiment of the foregoing embodiments, and the principle thereof is similar to that in the foregoing embodiments, and is not described here again.
In the embodiment of the present application, the provided method for calculating free energy of a molecule can be used to calculate different crystal forms of the molecule to be detected, respectively, by using the method for calculating free energy of a molecule to be detected provided in the foregoing embodiment, after obtaining initial coordinate data of different crystal forms of the molecule to be detected, and the change curves of free energy at different preset temperatures along with the volume are the same as those in the foregoing embodiment, and are not described herein again.
The technical scheme provided by the application can comprise the following beneficial effects: according to the embodiment of the application, the force field data of the molecule to be detected and the initial coordinate data of different crystal forms of the molecule to be detected are obtained, energy minimization processing is carried out on the different crystal forms of the molecule to be detected respectively, then under an isothermal and isobaric system, the vibration frequencies of all atoms in all coordinate directions of the different crystal forms of the molecule to be detected and the potential energies and the volumes of the different crystal forms of the molecule to be detected are calculated respectively, based on the vibration frequencies of all atoms in all coordinate directions of the different crystal forms of the molecule to be detected and the potential energies and the volumes of the different crystal forms of the molecule to be detected, the change curves of the free energy of the different crystal forms of the molecule to be detected along with the volumes are determined respectively by adopting a preset free energy calculation formula, and the free energy of the molecule crystal can be calculated accurately aiming at the molecular crystal with more atomic numbers, more flexible angles and anisotropy, and the calculation force and the calculation time are saved.
An embodiment of the present application provides a method for analyzing molecular stability, as shown in fig. 5, including:
step S501, obtaining absolute free energies of different crystal forms of the molecule to be detected at different preset temperatures by using the method in the foregoing embodiment.
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 detected at different temperatures may be respectively used, and the principle is not described herein again.
And S502, taking the absolute free energy of any crystal form at different preset temperatures as reference, and subtracting the reference from the absolute free energy of other crystal forms at the same preset temperature to obtain the relative free energy values of the crystal forms at different preset temperatures.
In the embodiment of the present application, for any crystal form of the molecule to be detected, the absolute free energy of the crystal form at different preset temperatures is taken as a reference, and the reference is subtracted from the absolute free energy of other crystal forms at the temperature, so as to obtain the relative free energy of each crystal form at each temperature.
Step S503, determining the most stable crystal form at a specific temperature based on the relative free energy values of the crystal forms at different preset temperatures, and taking the crystal form corresponding to the lowest relative free energy value at the same temperature as the most stable crystal form.
In the embodiment 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 detected at the temperature.
For the embodiment of the present application, for convenience of description, taking a specific embodiment as an example, as shown in fig. 6, a structural formula of a new crown pharmaceutical process pilavir (Favipiravir) molecule is shown, a molecular coordinate file of the molecule is obtained, where the file format may be a file of qbd format, a yoda program is used to capture corresponding GAFF force field data, a crystal structure cif file of one crystal form is obtained, the structure file is expanded to generate a 3x2x5 supercell, the force field data is read to generate an input file required by a gromacs (molecular dynamics method) program, the gromacs program is called to minimize energy of the supercell, the gromacs program is called again to perform NPT simulation on the supercell after energy minimization, the temperature is raised from 50K to 300K, 1fs and 7ns are simulated to obtain simulated trajectories, time trajectory corresponding to a specific temperature is extracted from the simulated trajectories at intervals of 10K, and NPT simulation is continued to perform NPT simulation, sd simulation is performed, the temperature reaches 1fs, and the final simulated temperature difference of each rmfs and the simulated displacement of a time trajectory is obtained as shown in a time displacement system, and a final displacement system is shown as a root mean square displacement graph, and a time displacement graph, which is shown as a root mean square displacement system, and a displacement graph, and a displacement system is obtained as a balance system is shown in a graph, wherein the graph, and a root mean square displacement system is shown as a system is shown below; invoking a gromacs program, selecting the average volume frame in the NPT simulation as input, sequentially performing energy minimization of a steepest descent method and a conjugate gradient method, ensuring that optimization reaches a convergence standard (for example, a gradient delta F is less than 0.001), and calculating potential energy (U) and a current volume (V); calling a gromacs program, taking the structure after the energy is minimized as an input, performing mode analysis, and calculating the vibration frequency (omega); the free energy versus volume curve for different temperatures was calculated using the following formula.
Wherein F (V, T) is free energy of the molecule to be detected at temperature T and volume V, U (V) is potential energy of the molecule to be detected at volume V, and N A Is the Avogastron constant, P is the ensemble pressure, k B Boltzmann constant, k (ω) is the frequency of the atom k,
to approximate the Planck constant, G (T) is expressed as the final free energy at temperature T.
The absolute free energy Δ Gabs (T) at this temperature can be determined from the minimum value of the free energy (F (V, T)) versus volume (V) curve at different temperatures (T), as shown in fig. 9. The above steps are repeated by using the coordinate files of different crystal forms of the molecule to be detected as input, and the relation of the relative free energy between different crystal forms along with the temperature change can be calculated, as shown in fig. 10. Meanwhile, for the same crystal form of the molecule, the relative free energy result obtained by PCSP calculation is shown in FIG. 11, the relative free energy trends of different structures at a low temperature section are basically consistent, but the calculation result of 50K-90K is inaccurate (not shown in the application) due to the limitation of the PSCP method, and the nuclear-time ratio used for calculating each structure by calculating the force field QHA and the PSCP method is 663/2958 which is about 0.22. The molecular free energy calculation method provided by the embodiment of the application saves about 80% of calculation cost while ensuring the correctness of the result.
Corresponding to the embodiment of the application function implementation method, the application also provides a molecular free energy calculation device, electronic equipment and a corresponding embodiment.
Fig. 12 is a schematic structural diagram of a molecular free energy calculation device according to an embodiment of the present application.
Referring to fig. 12, the molecular free energy calculation apparatus 120 includes an energy minimization module 1210, an equilibrium simulation module 1220, a curve calculation module 1230, and a free energy calculation module 1240, wherein:
the energy minimization module 1210 is configured 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 structural information of the first crystal form of the molecule to be detected after the energy minimization processing;
the balance simulation module 1220 is configured to calculate, by using a molecular dynamics method, vibration frequencies of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and potential energy and volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected after the energy minimization processing is in a balance state at a preset temperature based on the structural information of the first crystal form of the molecule to be detected after the energy minimization processing under an isothermal and isobaric ensemble;
a curve calculation module 1230, configured to determine a curve of change of free energy of the first crystal form of the molecule to be detected with the volume at multiple preset temperatures by using a preset free energy calculation formula based on the vibration frequency, the potential energy and the volume of the first crystal form of the molecule to be detected;
the free energy calculation module 1240 is configured to use a minimum free energy value in a variation curve of the free energy of the first crystal form of the molecule to be detected at each preset temperature along with the volume as an absolute free energy of the first crystal form of the molecule to be detected at the corresponding preset temperature.
As a possible implementation manner of the present application, in this embodiment, the energy minimization module 1210, when performing 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 to obtain the structure information of the first crystal form of the molecule to be detected after the energy minimization processing, may be configured to:
based on the force field data of the molecule to be detected and the structural data of the first crystal form of the molecule to be detected, carrying out cell expansion on the unit cell of the first crystal form of the molecule to be detected to obtain a supercell with a preset size;
and performing energy minimization on the supercell based on the force field data of the molecules to be detected to obtain the structural information of the supercell after the energy minimization.
As a possible implementation manner of this application, in this embodiment, the balance simulation module 1220, when calculating, by using a molecular dynamics method, a vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and a potential energy and a volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected after the energy minimization process is in an equilibrium state at a preset temperature under an isothermal and isobaric ensemble, based on the structural information of the first crystal form of the molecule to be detected after the energy minimization process, may be configured to:
performing isothermal isobaric ensemble simulation on the supercell subjected to the energy minimization treatment in a preset temperature interval to obtain a simulation track of the supercell of the first crystal form of the molecule to be detected;
selecting a plurality of temperature values in the preset temperature interval, selecting simulated track frames corresponding to the temperature values from simulated tracks of the supercell of the first crystal form of the molecule to be detected, and performing isothermal and isobaric ensemble simulation on the simulated track frames to obtain the volume of the first crystal form of the molecule to be detected in an equilibrium state under the temperature values;
calculating the average value of the volumes of the first crystal forms of the molecules to be detected in the equilibrium state under the temperature values respectively, selecting a target simulation track frame based on the average value, and performing energy minimization processing on the supercells of the first crystal forms of the molecules to be detected corresponding to the target simulation track frame to obtain the molecular structure after the energy minimization processing; selecting a simulation track frame corresponding to the simulation track frame and having the smallest error between the volume of the first crystal form of the molecule to be detected and the average value as a target simulation track frame;
and performing mode analysis on the molecular structure subjected to the energy minimization treatment, and calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction.
As a possible implementation manner of this application, in this embodiment, the balance simulation module 1220, when calculating, by using a molecular dynamics method, a vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and a potential energy and a volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected after the energy minimization process is in an equilibrium state at a preset temperature under an isothermal and isobaric ensemble, based on the structural information of the first crystal form of the molecule to be detected after the energy minimization process, may be configured to:
sequentially adopting a steepest descent method and a conjugate gradient method to carry out energy minimization processing on the target simulation track frame;
and when the energy minimization treatment reaches a preset standard, calculating the potential energy and the volume of the first crystal form of the molecule to be detected after the energy minimization treatment is carried out, and obtaining the potential energy and the volume of the first crystal form of the molecule to be detected.
As a possible implementation manner of the present application, in this embodiment, the molecular free energy calculating apparatus may be further configured to:
and aiming at any crystal form of the molecule to be detected, obtaining the absolute free energy corresponding to different crystal forms of the molecule to be detected at different preset temperatures by respectively adopting the method.
With regard to the apparatus in the above-described embodiment, the specific manner in which each module performs the operation has been described in detail in the embodiment related to the method, and will not be elaborated here.
The technical scheme provided by the application can comprise the following beneficial effects: the embodiment of the application can accurately calculate the free energy of the molecular crystal according to the change curve of the free energy of the first crystal form of the molecule to be detected along with the volume at a plurality of preset temperatures by acquiring the force field data of the molecule to be detected, performing energy minimization treatment on the first crystal form of the molecule to be detected, then calculating the vibration frequency of the first crystal form of the molecule to be detected in each coordinate direction and the potential energy and the volume of the first crystal form of the molecule to be detected under an isothermal and isobaric ensemble when the first crystal form of the molecule to be detected is in an equilibrium state at a preset temperature, and adopting a preset free energy calculation formula to determine the free energy of the first crystal form of the molecule to be detected along with the change curve of the volume at a plurality of preset temperatures aiming at more atomic numbers, more flexible angles and anisotropic molecular crystals, thereby saving calculation force and calculation time.
Fig. 13 is a schematic structural view of a molecular stability analysis apparatus according to 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:
an absolute free energy calculating unit 1310, configured to obtain absolute free energies of different crystal forms of the molecule to be detected at different preset temperatures by using the above method;
a relative free energy calculation unit 1320, configured to use the absolute free energy of any one of the crystal forms at different preset temperatures as a reference, and subtract the reference from the absolute free energy of the other crystal forms at the same preset temperature to obtain the relative free energy values of the crystal forms at different preset temperatures;
the stable crystal form determining unit 1330 is configured to determine, based on the relative free energy values of the crystal forms at different preset temperatures, a crystal form that is most stable at a specific temperature, and use a crystal form corresponding to the lowest relative free energy value at the same temperature as the most stable crystal form.
With regard to the apparatus in the above-described embodiment, the specific manner in which each module performs the operation has been described in detail in the embodiment related to the method, and will not be elaborated here.
According to the embodiment of the application, the relative free energy of different crystal forms of the same molecule is calculated, the crystal form with the lowest relative free energy at the same temperature is used as the most stable crystal form of the molecule at the temperature, and the stable state of the molecule at different temperatures can be accurately analyzed.
Fig. 14 is a schematic structural diagram of an electronic device shown in an embodiment of the present application.
Referring to fig. 14, the electronic device 1000 includes a memory 1010 and a processor 1020.
The Processor 1020 may be a Central Processing Unit (CPU), other general purpose Processor, a Digital Signal Processor (DSP), an Application Specific Integrated Circuit (ASIC), a Field Programmable Gate Array (FPGA) or other Programmable logic device, discrete Gate or transistor logic, 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 permanent storage. Wherein the ROM may store static data or instructions that are needed by the processor 1020 or other modules of the computer. The persistent storage device may be a read-write storage device. The persistent storage may be a non-volatile storage device that does not lose stored instructions and data even after the computer is powered down. In some embodiments, the persistent storage device employs a mass storage device (e.g., magnetic or optical disk, flash memory) as the persistent storage device. In other embodiments, the permanent storage may be a removable storage device (e.g., floppy disk, optical drive). The system memory may be a read-write memory device or a volatile read-write memory device, such as a dynamic random access memory. The system memory may store instructions and data that some or all of the processors require at runtime. Further, the memory 1010 may comprise any combination of computer-readable storage media, including various types of semiconductor memory chips (e.g., DRAM, SRAM, SDRAM, flash memory, programmable read-only memory), magnetic and/or optical disks, among others. In some embodiments, memory 1010 may include a removable storage device that is readable and/or writable, such as a Compact Disc (CD), a read-only digital versatile disc (e.g., DVD-ROM, dual layer DVD-ROM), a read-only Blu-ray disc, an ultra-density optical disc, a flash memory card (e.g., SD card, min SD card, micro-SD card, etc.), a magnetic floppy disc, or the like. Computer-readable storage media do not contain carrier waves or transitory electronic signals transmitted by wireless or wired means.
The memory 1010 has stored thereon executable code that, when processed by the processor 1020, may cause the processor 1020 to perform some or all of the methods described above.
Furthermore, the method according to the present application may also be implemented as a computer program or computer program product comprising computer program code instructions for performing some or all of the steps of the above-described method of the present application.
Alternatively, the present application may also be embodied as a computer-readable storage medium (or non-transitory machine-readable storage medium or machine-readable storage medium) having executable code (or a computer program or computer instruction code) stored thereon, which, when executed by a processor of an electronic device (or server, etc.), causes the processor to perform part or all of the steps of the above-described methods according to the present application.
Having described embodiments of the present application, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the disclosed embodiments. Many modifications and variations 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 was chosen in order to best explain the principles of the embodiments, the practical application, or improvements to the technology in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.
Claims (10)
1. A molecular free energy calculation method, comprising:
performing 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 adopting a molecular dynamics method to obtain the structural information of the first crystal form of the molecule to be detected after the energy minimization processing;
calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and the potential energy and the volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected subjected to the energy minimization treatment is in an equilibrium state at a preset temperature by adopting a molecular dynamics method based on the structural information of the first crystal form of the molecule to be detected subjected to the energy minimization treatment;
determining a change curve of the free energy of the first crystal form of the molecule to be detected along with the volume at a plurality of preset temperatures by adopting a preset free energy calculation formula based on the vibration frequency, the potential energy and the volume of the first crystal form of the molecule to be detected;
taking the minimum free energy value in the change curve of the free energy of the first crystal form of the molecule to be detected along with the volume at each preset temperature as the absolute free energy of the first crystal form of the molecule to be detected at the corresponding preset temperature;
the preset free energy calculation formula is as follows:
wherein the potential energy of the molecule to be detected is U, the volume is V, the vibration frequency is omega, F (V, T) is the free energy of the molecule to be detected at the temperature T and the volume V, U (V) is the potential energy of the molecule to be detected at the volume V, and N is N A Is the Avogastron constant, P is the ensemble pressure, K B Boltzmann constant, k (ω) is the frequency of the atom k,
to approximate the Planck constant, G (T) is expressed as the final free energy at temperature T.
2. The method according to claim 1, wherein the performing 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 to obtain the structural information of the first crystal form of the molecule to be detected after the energy minimization processing comprises:
based on the force field data of the molecule to be detected and the structural data of the first crystal form of the molecule to be detected, carrying out cell expansion on the unit cell of the first crystal form of the molecule to be detected to obtain a supercell with a preset size;
and performing energy minimization on the supercell based on the force field data of the molecules to be detected to obtain the structural information of the supercell after the energy minimization.
3. The method according to claim 2, wherein calculating, by using a molecular dynamics method, vibration frequencies of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and potential energy and volume of the first crystal form of the molecule to be detected when the energy-minimized first crystal form of the molecule to be detected is in an equilibrium state at a preset temperature under an isothermal and isobaric system based on the structural information of the energy-minimized first crystal form of the molecule to be detected comprises:
performing isothermal isobaric ensemble simulation on the supercell subjected to the energy minimization treatment in a preset temperature interval to obtain a simulation track of the supercell of the first crystal form of the molecule to be detected;
selecting a plurality of temperature values in the preset temperature interval, selecting simulated track frames corresponding to the temperature values from simulated tracks of the supercell of the first crystal form of the molecule to be detected, and performing isothermal and isobaric ensemble simulation on the simulated track frames to obtain the volume of the first crystal form of the molecule to be detected in an equilibrium state under the temperature values;
calculating the average value of the volumes of the first crystal forms of the molecules to be detected in the equilibrium state under the temperature values respectively, selecting a target simulation track frame based on the average value, and performing energy minimization processing on the supercells of the first crystal forms of the molecules to be detected corresponding to the target simulation track frame to obtain the molecular structure after the energy minimization processing; selecting a simulation track frame corresponding to the simulation track frame and having the smallest error between the volume of the first crystal form of the molecule to be detected and the average value as a target simulation track frame;
and performing mode analysis on the molecular structure subjected to the energy minimization treatment, and calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction.
4. The method according to claim 3, wherein calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and the potential energy and volume of the first crystal form of the molecule to be detected when the energy-minimized first crystal form of the molecule to be detected is in an equilibrium state at a preset temperature by using a molecular dynamics method based on the structural information of the energy-minimized first crystal form of the molecule to be detected, under an isothermal and isobaric system, comprises:
sequentially adopting a steepest descent method and a conjugate gradient method to carry out energy minimization processing on the target simulation track frame;
and when the energy minimization treatment reaches a preset standard, calculating the potential energy and the volume of the first crystal form of the molecule to be detected after the energy minimization treatment is carried out, and obtaining the potential energy and the volume of the first crystal form of the molecule to be detected.
5. The method of calculating the free energy of a molecule according to any one of claims 1 to 4, further comprising:
and aiming at any crystal form of the molecule to be detected, respectively adopting the method of any one of claims 1 to 4 to obtain the corresponding absolute free energy of different crystal forms of the molecule to be detected at different preset temperatures.
6. A method for analyzing molecular stability, comprising:
obtaining absolute free energies of different crystal forms of the molecule to be detected at different preset temperatures by using the method of claim 5;
taking the absolute free energy of any crystal form 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 relative free energy values of the crystal forms at different preset temperatures;
and determining the most stable crystal form at a specific temperature based on the relative free energy values of the crystal forms at different preset temperatures, and taking the crystal form which corresponds to the lowest relative free energy value at the same temperature as the most stable crystal form.
7. A molecular free energy computing device, the device comprising:
the energy minimization module is used for performing 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 adopting a molecular dynamics method to obtain the structural information of the first crystal form of the molecule to be detected after the energy minimization processing;
the balance simulation module is used for calculating the vibration frequency of all atoms of the first crystal form of the molecule to be detected in each coordinate direction and the potential energy and the volume of the first crystal form of the molecule to be detected when the first crystal form of the molecule to be detected after the energy minimization treatment is in a balance state at a preset temperature under an isothermal and isobaric ensemble by adopting a molecular dynamics method based on the structural information of the first crystal form of the molecule to be detected after the energy minimization treatment;
the curve calculation module is used for determining a free energy change curve of the first crystal form of the molecule to be detected along with the volume at a plurality of preset temperatures by adopting a preset free energy calculation formula based on the vibration frequency, the potential energy and the volume of the first crystal form of the molecule to be detected;
the free energy calculation module is used for taking the minimum free energy value in the change curve of the free energy of the first crystal form of the molecule to be detected along with the volume at each preset temperature as the absolute free energy of the first crystal form of the molecule to be detected at the corresponding preset temperature;
the preset free energy calculation formula is as follows:
wherein the potential energy of the molecule to be detected is U, the volume is V, the vibration frequency is omega, F (V, T) is the free energy of the molecule to be detected at the temperature T and the volume V, U (V) is the potential energy of the molecule to be detected at the volume V, and N is N A Is an Avogadro constant, P is the ensemble pressure, K B Boltzmann constant, k (ω) is the frequency of the atom k,
to approximate the Planck constant, G (T) is expressed as the final free energy at temperature T.
8. A molecular stability analysis device, comprising:
an absolute free energy calculation unit, configured to obtain absolute free energies of different crystal forms of the molecule to be detected at different preset temperatures by using the method according to claim 4;
the relative free energy calculation unit is used for subtracting the reference from the absolute free energy of other crystal forms at the same preset temperature by taking the absolute free energy of any crystal form at different preset temperatures as the reference to obtain the relative free energy values of all crystal forms at different preset temperatures;
and the stable crystal form determining unit is used for determining the most stable crystal form at a specific temperature based on the relative free energy values of the crystal forms at different preset temperatures, and taking the crystal form which corresponds to the lowest relative free energy value at the same temperature as the most stable crystal form.
9. An apparatus, comprising:
a processor; and
a memory having executable code stored thereon, which when executed by the processor, causes the processor to perform the method of any one of claims 1-6.
10. A storage medium having stored thereon executable code which, when executed by a processor of an electronic device, causes the processor to perform the method of any one of claims 1-6.
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