WO2023102870A1 - Procédé et appareil de calcul d'énergie libre d'une molécule, et procédé et appareil d'analyse de stabilité, et dispositif et support de stockage - Google Patents

Procédé et appareil de calcul d'énergie libre d'une molécule, et procédé et appareil d'analyse de stabilité, et dispositif et support de stockage Download PDF

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WO2023102870A1
WO2023102870A1 PCT/CN2021/136976 CN2021136976W WO2023102870A1 WO 2023102870 A1 WO2023102870 A1 WO 2023102870A1 CN 2021136976 W CN2021136976 W CN 2021136976W WO 2023102870 A1 WO2023102870 A1 WO 2023102870A1
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molecule
crystal form
energy
measured
free energy
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PCT/CN2021/136976
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Chinese (zh)
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周天
彭春望
方利文
孙广旭
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上海智药科技有限公司
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C10/00—Computational theoretical chemistry, i.e. ICT specially adapted for theoretical aspects of quantum chemistry, molecular mechanics, molecular dynamics or the like

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  • 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.
  • Crystal Structure Predict 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.
  • 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.
  • calculation methods such as harmonic approximation method, quasi-harmonic approximation method, and pseudo-supercritical path method, but these methods generally have some problems.
  • 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.
  • the first aspect of the present application provides a molecular free energy calculation method, including:
  • 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.
  • 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:
  • the energy minimization process is performed on the supercell to obtain the structural information of the supercell after the energy minimization process.
  • 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:
  • 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;
  • 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.
  • 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:
  • the method further includes:
  • 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:
  • 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.
  • 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.
  • 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 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:
  • 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.
  • 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.
  • 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.
  • FIG. 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.
  • 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.
  • first information may also be called second information, and similarly, second information may also be called first information.
  • second information may also be called first information.
  • a feature defined as “first” and “second” may explicitly or implicitly include one or more of these features.
  • “plurality” means two or more, unless otherwise specifically defined.
  • HA Harmonic Approximation
  • QHA Quasi Harmonic Approximation
  • PSCP pseudo-supercritical path
  • 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.
  • 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
  • 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.
  • 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.
  • the molecular crystal free energy calculation method 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.
  • 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.
  • 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.
  • 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.
  • the molecules to be measured are in different crystal type, the corresponding initial coordinate data are different.
  • 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
  • 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.
  • the isothermal and isobaric ensemble is an ensemble with controllable temperature and controllable pressure.
  • 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.
  • 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.
  • 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.
  • 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.
  • the calculated potential energy of the molecule to be measured is U
  • the volume is V
  • the vibration frequency is ⁇
  • the preset free energy formula can be as follows:
  • 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
  • P is the system Comprehensive pressure
  • k B is the Boltzmann constant
  • k( ⁇ ) is the frequency of atom k
  • G(T) is expressed as the final free energy at temperature T.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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
  • the preset size of the supercell is a 3 ⁇ 2 ⁇ 5 supercell.
  • 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.
  • 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.
  • the pre-set gromacs program 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • the selected temperature range multiple temperature values are selected, and in a specific implementation
  • the selected temperature values are 50K, 60K, 70K, 80K, etc.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • the molecular dynamics method is adopted.
  • the energy minimization reaches the preset standard, such as gradient ⁇ F ⁇ 0.001
  • the method further includes:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystal form with the lowest relative free energy is the most stable crystal form of the molecule to be tested at that temperature.
  • Figure 6 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.
  • the yoda program 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
  • 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 ⁇ F ⁇ 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 ( ⁇ ); use the following formula to calculate the curve of free energy versus volume at different temperatures.
  • the convergence standard such as gradient ⁇ F ⁇ 0.001
  • U potential energy
  • V current volume
  • 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
  • P is the system Comprehensive pressure
  • k B is the Boltzmann constant
  • k( ⁇ ) is the frequency of atom k
  • G(T) is expressed as the final free energy at temperature T.
  • the absolute free energy ⁇ Gabs(T) at the temperature can be obtained, as shown in Figure 9.
  • the relationship between the relative free energy of different crystal forms with temperature can be calculated, as shown in Figure 10.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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:
  • the energy minimization process is performed on the supercell to obtain the structural information of the supercell after the energy minimization process.
  • 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:
  • 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;
  • 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.
  • 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:
  • the molecular free energy calculation device can also be used for:
  • 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.
  • the technical solution provided by the present application may include the following beneficial effects:
  • 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.
  • 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.
  • 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.
  • FIG. 14 is a schematic structural diagram of an electronic device shown in an embodiment of the present application.
  • 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.
  • 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.
  • the permanent storage device adopts a mass storage device (such as a magnetic or optical disk, flash memory) as the permanent storage device.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • executable code or computer program or computer instruction code
  • 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.

Abstract

La présente demande concerne un procédé et un appareil de calcul de l'énergie libre d'une molécule, et un procédé et un appareil d'analyse de stabilité, et un dispositif électronique et un support de stockage. Le procédé de calcul de l'énergie libre d'une molécule consiste : à réaliser un traitement de minimisation d'énergie sur une molécule à l'essai; sous un ensemble isotherme-isobare, lorsque ladite molécule est dans un état équilibré à une température prédéfinie, à calculer la fréquence de vibration de ladite molécule dans chaque direction de coordonnées; à calculer l'énergie potentielle et le volume de ladite molécule; et sur la base des fréquences de vibration, et l'énergie potentielle et le volume de ladite molécule, à déterminer une courbe de l'énergie libre de ladite molécule changeant, à la température prédéfinie, conjointement avec le volume. Au moyen des modes de réalisation de la présente demande, pour des cristaux moléculaires anisotropes présentant plus d'atomes et des angles flexibles, l'énergie libre des cristaux moléculaires peut être calculée avec précision, ce qui permet d'économiser la puissance de calcul et le temps de calcul.
PCT/CN2021/136976 2021-12-10 2021-12-10 Procédé et appareil de calcul d'énergie libre d'une molécule, et procédé et appareil d'analyse de stabilité, et dispositif et support de stockage WO2023102870A1 (fr)

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CN107004064A (zh) * 2014-09-30 2017-08-01 国立大学法人大阪大学 自由能计算装置、方法、程序、以及记录有该程序的记录介质
US20200134246A1 (en) * 2018-05-10 2020-04-30 Shenzhen Jingtai Technology Co., Ltd. Gromacs cloud computing process control method
CN112199909A (zh) * 2020-10-22 2021-01-08 深圳晶泰科技有限公司 一种准确计算气体分子绝对自由能的方法
US20210193270A1 (en) * 2019-12-20 2021-06-24 International Business Machines Corporation Quantum computing thermodynamic observables of a chemical system

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107004064A (zh) * 2014-09-30 2017-08-01 国立大学法人大阪大学 自由能计算装置、方法、程序、以及记录有该程序的记录介质
US20200134246A1 (en) * 2018-05-10 2020-04-30 Shenzhen Jingtai Technology Co., Ltd. Gromacs cloud computing process control method
US20210193270A1 (en) * 2019-12-20 2021-06-24 International Business Machines Corporation Quantum computing thermodynamic observables of a chemical system
CN112199909A (zh) * 2020-10-22 2021-01-08 深圳晶泰科技有限公司 一种准确计算气体分子绝对自由能的方法

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