WO2023108622A1 - 获得电荷参数的方法、分子力学模拟结果的方法及装置 - Google Patents

获得电荷参数的方法、分子力学模拟结果的方法及装置 Download PDF

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WO2023108622A1
WO2023108622A1 PCT/CN2021/139227 CN2021139227W WO2023108622A1 WO 2023108622 A1 WO2023108622 A1 WO 2023108622A1 CN 2021139227 W CN2021139227 W CN 2021139227W WO 2023108622 A1 WO2023108622 A1 WO 2023108622A1
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molecules
charge
electrostatic potential
environmental
target molecule
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PCT/CN2021/139227
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French (fr)
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方栋
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深圳晶泰科技有限公司
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Publication of WO2023108622A1 publication Critical patent/WO2023108622A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R29/00—Arrangements for measuring or indicating electric quantities not covered by groups G01R19/00 - G01R27/00
    • G01R29/24—Arrangements for measuring quantities of charge

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  • the application belongs to the technical field of molecular simulation, and specifically relates to a method for obtaining charge parameters, a method and a device for molecular mechanics simulation results.
  • the molecular force field is an indispensable part of molecular mechanics, and the quality of the parameters in the molecular force field directly determines the accuracy of molecular mechanics simulation results.
  • the traditional molecular force field contains bonding items (eg, bond length, bond angle, dihedral angle, etc.) and non-bonding items (eg, charge interaction, van der Waals interaction, etc.). In the process of binding non-covalent drug molecules and protein molecules, non-bonding items, especially charge interactions, play a crucial role.
  • the molecular force field calculation of the charge action requires the charge parameters in the force field, and currently the point charge model is generally used to calculate the charge parameters.
  • the general way to obtain point charges is based on the gas phase, that is, a single molecule is obtained by fitting the space potential generated by quantum chemical methods in an isolated environment. But in real biological application scenarios, the process that needs to be simulated is often in solution (usually water) or protein environment. These environments will affect the potential distribution of the small molecule itself, resulting in a different space potential from that in the gas phase. That is, the charge parameters obtained by fitting in the gas phase may bring inaccurate results in the actual complex environment.
  • the application provides a method for obtaining charge parameters, a method and a device for molecular mechanics simulation results, and obtains charge parameters by considering the environment in which solute molecules are located, so as to improve the accuracy of molecular mechanics simulation results of solute molecules in their environment Spend.
  • a technical solution adopted by the present application is to provide a method for obtaining charge parameters, including: S1, performing structural optimization on solute molecules to obtain at least one target molecule, and obtaining the Initial electrostatic potential charge; S2, for each of the target molecules, construct a simulation system based on the target molecule and a plurality of environmental molecules; wherein, the target molecule is surrounded by a plurality of environmental molecules; S3, using the initial Electrostatic potential charges perform molecular dynamics simulation on the simulation system to at least obtain the coordinate information of the environmental molecules at multiple moments in the simulation process; S4, based on the coordinate information of the environmental molecules at multiple moments and the Obtain the first electrostatic potential charge of the target molecule based on the charge amount of each atom in the environmental molecule; S5, judge whether the first electrostatic potential charge and the initial electrostatic potential charge meet the first preset condition; S6, if so, Use the first electrostatic potential charge as the charge parameter when the target molecule is surrounded by the environmental molecules; S7, otherwise, use the first
  • another technical solution adopted by the present application is to provide a method for obtaining molecular mechanics simulation results, including: using the method described in any of the above-mentioned embodiments to obtain the charge parameters of solute molecules; The charge parameter obtains molecular mechanics simulation results of the solute molecules and the environment molecules.
  • a device for obtaining charge parameters including: a first obtaining module, which is used to optimize the structure of solute molecules to obtain at least one of the target molecules, and Obtain the initial electrostatic potential charge of each of the target molecules; a construction module, connected to the first acquisition module, for each of the target molecules, based on the target molecule and a plurality of environmental molecules to build a simulation system; wherein , the target molecule is surrounded by a plurality of the environmental molecules; a second acquisition module, connected to the building module, is used to perform a molecular dynamics simulation on the simulation system using the initial electrostatic potential charge, so as to obtain at least a simulation
  • the coordinate information of the environmental molecules at multiple moments in the process; the third obtaining module, connected to the second obtaining module, is used to obtain coordinate information based on the environmental molecules at multiple moments and in the environmental molecules
  • the charge amount of each atom obtains the first electrostatic potential charge of the target molecule; the judging module is
  • an electronic device including a memory and a processor coupled to each other, the memory stores program instructions, and the processor is used to execute the program instructions to implement the method for obtaining charge parameters described in any of the above embodiments, or the method for obtaining molecular mechanics simulation results.
  • another technical solution adopted by this application is to provide a storage device storing program instructions that can be executed by a processor, and the processor is used to execute the program instructions to realize any of the above-mentioned embodiments
  • the method for obtaining charge parameters as described in or the method for obtaining molecular mechanics simulation results as described.
  • the beneficial effect of the present application is: the process of the method for obtaining the charge parameters in the present application includes: optimizing the structure of the solute molecule to obtain at least one target molecule, and obtaining the initial electrostatic potential of each target molecule charge; for each target molecule, construct a simulation system based on the target molecule and a plurality of environmental molecules; wherein, the target molecule is surrounded by a plurality of environmental molecules; use the initial electrostatic potential charge to simulate The system performs molecular dynamics simulation to at least obtain the coordinate information of the environmental molecules at multiple moments in the simulation process; based on the coordinate information of the environmental molecules at multiple moments and the charge of each atom in the environmental molecules Obtaining the first electrostatic potential charge of the target molecule; judging whether the first electrostatic potential charge and the initial electrostatic potential charge meet the first preset condition; if so, using the first electrostatic potential charge as the target molecule The charge parameter when surrounded by the environmental molecules; otherwise, use the first electrostatic potential charge as the initial electrostatic potential charge
  • FIG. 1 is a schematic flow diagram of an embodiment of a method for obtaining charge parameters in the present application
  • FIG. 2 is a schematic flow diagram of an embodiment of optimizing the structure of solute molecules to obtain at least one target molecule in step S1 in FIG. 1;
  • Fig. 3 is a schematic flow chart of an embodiment of optimizing the structure of solute molecules to obtain at least one target molecule in step S1 in Fig. 1;
  • Fig. 4 is a schematic flow chart of an embodiment corresponding to step S3 in Fig. 1;
  • Fig. 5 is a schematic flow chart of an embodiment corresponding to step S4 in Fig. 1;
  • FIG. 6 is a schematic flow diagram of an embodiment of a method for obtaining molecular mechanics simulation results in the present application
  • FIG. 7 is a schematic structural diagram of an embodiment of a device for obtaining charge parameters in the present application.
  • FIG. 8 is a schematic structural diagram of an embodiment of an electronic device of the present application.
  • FIG. 9 is a schematic structural diagram of an embodiment of a storage device of the present application.
  • FIG. 1 is a schematic flow chart of an embodiment of a method for obtaining charge parameters in the present application. The method includes:
  • S1 Perform structure optimization on solute molecules to obtain at least one target molecule, and obtain the initial electrostatic potential charge of each target molecule.
  • FIG. 2 is a schematic flowchart of an embodiment of performing structure optimization on solute molecules in step S1 in FIG. 1 to obtain at least one target molecule.
  • the process of optimizing the structure of solute molecules in the above step S1 to obtain at least one target molecule specifically includes:
  • environmental molecules may include organic solvent molecules or inorganic solvent molecules or protein molecules, etc.; wherein, organic solvent molecules include methanol, ethanol, benzene, ether, dichloromethane, acetone, tetrahydrofuran, ethyl acetate, acetonitrile or toluene, etc. ; Inorganic solvent molecules include water, ammonia, hydrogen fluoride, or sulfur dioxide.
  • organic solvent molecules include methanol, ethanol, benzene, ether, dichloromethane, acetone, tetrahydrofuran, ethyl acetate, acetonitrile or toluene, etc.
  • Inorganic solvent molecules include water, ammonia, hydrogen fluoride, or sulfur dioxide.
  • the above-mentioned implicit solvent model can be Onsager (Onsager model), PCM (Polarizable continuum model, polar continuum model), CPCM (conductor-like polarizable continuum model, conductor polar continuum model) , IPCM (isodensity polarizable continuum model, equal density polarizable continuum model), SCIPCM (self-consistent isodensity polarizable continuum model, self-consistent isodensity polarizable continuum model), COSMO (conductor-like screening model, similar conductor shielding model ), SMD (solvation model based on density, density-based solvent model), etc.
  • Onsager model Onsager model
  • PCM Polyrizable continuum model, polar continuum model
  • CPCM conductor-like polarizable continuum model, conductor polar continuum model
  • IPCM isodensity polarizable continuum model, equal density polarizable continuum
  • the implicit solvent model is a model that regards solvent molecules (i.e., environmental molecules) as a continuous medium, that is, it does not specifically describe the specific structure and distribution of environmental molecules near solute molecules, but simply regards the surrounding environment as a Polarizable continuum is considered.
  • solvent molecules i.e., environmental molecules
  • the advantage of considering the solvent effect is that it can express the average effect of the solvent without considering the arrangement of various possible solvent layer molecules like the explicit solvent model, and it will not increase the calculation time.
  • S202 Place the solute molecules in the implicit solvent model for structural optimization to obtain target molecules with the lowest local energy.
  • the Hartree-Fock (HF, Hartree-Fock) method in open source quantum chemical calculation software can be used for structure optimization to obtain the target molecule with the lowest local energy .
  • open source quantum chemical calculation software such as NWChem, GAMESS, Gaussian, etc.
  • the initial electrostatic potential (ESP) charge Q0 of the target molecule and the coordinates of each atom in the target molecule can also be obtained by using the current quantum chemical calculation software.
  • the NWChem software when operating the NWChem software, you can directly select the keyword "task esp" to obtain the initial electrostatic potential charge Q0 of the target molecule.
  • FIG. 3 is a schematic flowchart of an embodiment of optimizing the structure of solute molecules to obtain at least one target molecule in step S1 in FIG. 1 .
  • the process of optimizing the structure of solute molecules in the above step S1 to obtain at least one target molecule specifically includes:
  • S301 performing dihedral angle rotation on solute molecules to obtain multiple molecules with different conformations.
  • the implementation process of the above step S302 may be: firstly, construct an implicit solvent model based on multiple environmental molecules; this step is similar to the above step S201, and will not be described in detail here. Next, place the conformational molecules in the implicit solvent model for structural optimization to obtain the target molecule with the lowest local energy; this step is similar to the above step S202 and will not be described in detail here.
  • S303 Merge the same three-dimensional structure molecules in all optimized structure molecules to obtain at least one target molecule.
  • the three-dimensional structures of the optimized structure molecules corresponding to all conformational molecules may be the same, and in this case, the number of target molecules finally obtained after merging is one.
  • the conformational molecules formed by the dihedral angle rotation of the solute molecule A include A, A1, A2, and A3, and the optimized structure molecules corresponding to the conformational molecules A, A1, A2, and A3 are all B, then the target molecule is B at this time.
  • the three-dimensional structures of the optimized structure molecules corresponding to all conformational molecules may include at least two types, and at this time, the number of target molecules finally obtained through merging is at least two types.
  • the conformational molecules formed by solute molecule A after dihedral rotation include A, A1, A2, and A3, the optimized structure molecules corresponding to conformational molecules A and A1 are both B, and the optimized structural molecules corresponding to conformational molecules A2 and A3 are B1, then the target molecules are B and B1 at this time.
  • S2 For each target molecule, construct a simulation system based on the target molecule and multiple environmental molecules; wherein, the target molecule is surrounded by multiple environmental molecules.
  • the step of constructing a simulation system based on the target molecule and multiple environmental molecules in the above step S2 includes: constructing an explicit solvent model based on multiple environmental molecules; placing the target molecule in the explicit solvent model, Get a mock system.
  • the above explicit solvent model can be TIP3P (transferable inmolecular potential 3 point, 3 point model of transferable intermolecular potential), TIP4P (transferable intermolecular potential 4 point, 4 point model of transferable intermolecular potential) , TIP5P (transferable inmolecular potential 5 point, transferable intermolecular potential 5 point model), etc.
  • the explicit solvent model is a model that simulates each solvent molecule (that is, an environmental molecule) as a separate molecule; that is, each environmental molecule in the explicit solvent model is a separate molecule, and the environmental molecule can be considered by using the explicit solvent model The effect of each atom in the solute molecule on the charge parameters in order to improve the accuracy of the charge parameters obtained subsequently.
  • S3 Perform molecular dynamics simulation on the simulated system by using the initial electrostatic potential charge, so as to at least obtain coordinate information of environmental molecules at multiple moments during the simulation process.
  • FIG. 4 is a schematic flowchart of an embodiment corresponding to step S3 in FIG. 1.
  • the above step S3 specifically includes:
  • S401 Initialize the molecular dynamics model by using the initial electrostatic potential charge.
  • the dynamics model built into the molecular dynamics software GROMACS can be used for dynamics simulation; and at this time, the charge parameter in the kinetics model is the initial electrostatic potential charge Q0.
  • S402 Perform dynamics simulation on the simulation system based on the initialized molecular dynamics model, and keep the coordinates of each atom in the target molecule unchanged during the simulation process, and only allow the coordinates of each atom in the environment molecule to change.
  • the coordinates of each atom in the target molecule can be the same as the coordinates of the target molecule obtained in step S1; that is, the position of the target molecule in steps S1 and S3 can be kept unchanged.
  • the predetermined simulation time range may be 2 nanoseconds, and the predetermined time interval may be 10 picoseconds.
  • the coordinates of each atom in all environmental molecules at 200 moments may be obtained.
  • the above method of keeping the coordinates of each atom in the target molecule unchanged can make the method of obtaining the first electrostatic potential charge in the subsequent step S4 relatively simple, and the calculation amount is relatively small.
  • S4 Obtain the first electrostatic potential charge of the target molecule based on the coordinate information of the environmental molecule at multiple times and the charge amount of each atom in the environmental molecule.
  • step S4 specifically comprises:
  • S501 Use the coordinates of each atom in all environmental molecules at each time as the coordinates of multiple point charges outside the target molecule, and compare the charge amount of each atom in all environmental molecules at each time with the number of multiple times The second ratio is taken as the charge amount of the point charge at the corresponding position.
  • each atom in the environmental molecules there are 100 environmental molecules around the current solute molecule, and the charges of each atom in the environmental molecules can be the same or different.
  • the environmental molecules are water molecules, each water molecule has 3 atoms, the charge of the oxygen atom in the water molecule is -0.8, and the charge of the hydrogen atom in the water molecule is 0.4. Then there are 3*100 point charges in the current environment at the same time.
  • the environmental molecular coordinates at 200 moments are obtained in step S3
  • S502 Obtaining a first electrostatic potential charge based on the coordinates of multiple point charges outside the target molecule and their charge quantities.
  • the first electrostatic potential charge Q1 can be obtained by calculating and fitting the single point energy of the quantum chemical HF method.
  • step S3 when the position of the target molecule also moves during the kinetic simulation in step S3, the position of the simulation system at multiple moments can be moved first, and the target molecule in the simulation system Molecules of the environment will move in sync.
  • step S501 When the position of the target molecule at each time is the same, go to step S501.
  • the specific implementation process of the above step S5 may be: judging whether the average variance between the first electrostatic potential charge Q1 and the initial electrostatic potential charge Q0 is smaller than a threshold; optionally, the threshold may be 0.01 or the like. This design method requires less calculation.
  • the specific implementation process of the above step S5 may also be: judging whether the standard deviation between the first electrostatic potential charge Q1 and the initial electrostatic potential charge Q0 is less than a threshold value, which is not limited in this application.
  • step S7 Otherwise, use the first electrostatic potential charge as the initial electrostatic potential charge, and return to step S3.
  • step S1 the implicit solvent model with fast calculation rate but not so high accuracy is used for calculation, and then the explicit solvent model with slow calculation rate but high accuracy rate is used for calculation, which can improve the effect of the whole method , including efficiency and accuracy.
  • step S7 it may also include: obtaining the sum value of the charge parameters corresponding to all target molecules; combining the sum value with the number of target molecules The first ratio serves as a charge parameter when solute molecules are surrounded by environmental molecules. This design method can further improve the accuracy of the charge parameters of solute molecules.
  • FIG. 6 is a schematic flow chart of an embodiment of a method for obtaining molecular mechanics simulation results in the present application.
  • the above-mentioned method specifically includes:
  • the implementation process of the above step S601 may refer to the method for obtaining the charge parameter mentioned in any of the above embodiments.
  • the obtained first result when using the charge parameters obtained in step S601 to calculate some solvation-related properties such as hydration free energy (ie, the free energy required for molecules to dissolve in water from the gas phase), the obtained first result ; Compared with the second result obtained by calculating the charge parameters obtained by the gas phase method, the first result is closer to the experimental value than the second result.
  • some solvation-related properties such as hydration free energy (ie, the free energy required for molecules to dissolve in water from the gas phase)
  • the method for obtaining charge parameters provided by this application is applied to the Freesolv data set, and the charge parameters in the force field (generated by the AM1-BCC model) are replaced by the charge parameters that consider the water environment generated by the process in Figure 1, while retaining other parameters in the force field, the average variance between the calculated value and the experimental value of the final hydration free energy is 1.12kcal/mol.
  • the charge parameter is obtained by the gas phase method, the average variance between the calculated free energy of hydration and the experimental value is 1.51kcal/mol. The smaller variance shows that the calculated value is more consistent with the experimental value, and the new charge parameter acquisition process provided by this application brings more accurate calculated value.
  • FIG. 7 is a schematic structural diagram of an embodiment of a device for obtaining charge parameters in the present application.
  • the above-mentioned device for obtaining charge parameters includes a first obtaining module 10, a building module 12, a second obtaining module 14, and a third obtaining module 16. , a judgment module 18 and an execution module 11.
  • the first obtaining module 10 is used to optimize the structure of solute molecules to obtain at least one target molecule, and obtain the initial electrostatic potential charge of each target molecule.
  • the construction module 12 is connected with the first acquisition module 10, and is used for constructing a simulation system based on the target molecule and multiple environmental molecules for each target molecule; wherein, the target molecule is surrounded by multiple environmental molecules.
  • the second obtaining module 14 is connected with the building module 12, and is used for performing molecular dynamics simulation on the simulation system by using the initial electrostatic potential charge, so as to at least obtain coordinate information of environmental molecules at multiple moments during the simulation process.
  • the third obtaining module 16 is connected with the second obtaining module 14, and is used for obtaining the first electrostatic potential charge of the target molecule based on the coordinate information of the environmental molecule at multiple times and the charge amount of each atom in the environmental molecule.
  • the judging module 18 is connected to the third obtaining module 16, and is used for judging whether the first electrostatic potential charge and the initial electrostatic potential charge meet the first preset condition.
  • the execution module 11 is connected with the judgment module 18, and is used to use the first electrostatic potential charge as the charge parameter when the target molecule is surrounded by environmental molecules when the judgment module is judged to be yes; An electrostatic potential charge is used as the initial electrostatic potential charge and returned to the step of performing molecular dynamics simulation on the simulated system using the initial electrostatic potential charge.
  • the above-mentioned first obtaining module 10 is specifically configured to construct an implicit solvent model based on multiple environmental molecules; place solute molecules in the implicit solvent model for structural optimization, and obtain target molecules with the lowest local energy.
  • the first obtaining module 10 is specifically used to perform dihedral angle rotation on solute molecules to obtain a plurality of different conformational molecules; perform structural optimization on each conformational molecule to obtain corresponding optimized structural molecules; Molecules with the same three-dimensional structure are combined to obtain at least one target molecule.
  • the above-mentioned building block 12 is specifically configured to construct an explicit solvent model based on a plurality of environmental molecules; placing target molecules in the explicit solvent model to obtain a simulation system.
  • the above-mentioned second obtaining module 14 is specifically configured to use the initial electrostatic potential charge to initialize the molecular dynamics model; perform dynamics simulation on the simulation system based on the initialized molecular dynamics model, and keep the target molecule during the simulation process The coordinates of each atom in the system remain unchanged, and only the coordinates of each atom of the environmental molecule are allowed to change; within the predetermined simulation time range, the coordinates of each atom in all environmental molecules at the current moment are saved at each predetermined time interval.
  • the above-mentioned third obtaining module 16 is specifically configured to use the coordinates of each atom in all environmental molecules at each moment as the coordinates of multiple point charges outside the target molecule, and use The second ratio of the charge amount of each atom to the number of multiple moments is used as the charge amount of the point charge at the corresponding position; the first electrostatic potential charge is obtained based on the coordinates of the multiple point charges outside the target molecule and their charge amount fitting .
  • the judging module 18 is specifically configured to judge whether an average variance between the first electrostatic potential charge and the initial electrostatic potential charge is smaller than a threshold.
  • the above-mentioned device may also include a fourth obtaining module, connected to the execution module 18, for obtaining the sum value of the charge parameters corresponding to all target molecules; combining the sum value with the target molecule The first ratio of the number of is used as the charge parameter when solute molecules are surrounded by environment molecules.
  • FIG. 8 is a schematic structural diagram of an embodiment of the electronic device of the present application.
  • the electronic device includes: a memory 22 and a processor 20 coupled to each other.
  • Program instructions are stored in the memory 22, and the processor 20 is used to execute the program. Instructions to implement any of the above methods for obtaining charge parameters, or methods for obtaining molecular mechanics simulation results.
  • electronic devices include but are not limited to: desktop computers, notebook computers, tablet computers, servers, etc., which are not limited here.
  • the processor 20 may also be referred to as a CPU (Center Processing Unit, central processing unit).
  • the processor 20 may be an integrated circuit chip with signal processing capability.
  • the processor 20 can also be, a general-purpose processor, a digital signal processor (Digital Signal Processor, DSP), an application specific integrated circuit (Application Specific Integrated Circuit, ASIC), a field-programmable gate array (Field-Programmable Gate Array, FPGA) or Other programmable logic devices, discrete gate or transistor logic devices, discrete hardware components.
  • DSP Digital Signal Processor
  • ASIC Application Specific Integrated Circuit
  • FPGA Field-Programmable Gate Array
  • a general-purpose processor may be a microprocessor, or the processor may be any conventional processor, or the like.
  • the processor 20 may be jointly realized by an integrated circuit chip.
  • FIG. 9 is a schematic structural diagram of an embodiment of a storage device of the present application.
  • the storage device 30 stores program instructions 300 that can be executed by a processor.
  • the program instructions 300 are used to implement any of the above methods for obtaining charge parameters. Or a method to obtain the results of molecular mechanics simulations.
  • the disclosed methods and devices may be implemented in other ways.
  • the device implementations described above are only illustrative.
  • the division of modules or units is only a logical function division. In actual implementation, there may be other division methods.
  • multiple units or components can be combined or May be integrated into another system, or some features may be ignored, or not implemented.
  • the mutual coupling or direct coupling or communication connection shown or discussed may be through some interfaces, and the indirect coupling or communication connection of devices or units may be in electrical, mechanical or other forms.
  • a unit described as a separate component may or may not be physically separated, and a component shown as a unit may or may not be a physical unit, that is, it may be located in one place, or may be distributed to multiple network units. Part or all of the units can be selected according to actual needs to achieve the purpose of the solution of this embodiment.
  • each functional unit in each embodiment of the present application may be integrated into one processing unit, each unit may exist separately physically, or two or more units may be integrated into one unit.
  • the above-mentioned integrated units can be implemented in the form of hardware or in the form of software functional units.
  • the integrated unit is realized in the form of a software function unit and sold or used as an independent product, it can be stored in a computer-readable storage medium.
  • the technical solution of the present application is essentially or part of the contribution to the prior art or all or part of the technical solution can be embodied in the form of a software product, and the computer software product is stored in a storage medium , including several instructions to make a computer device (which may be a personal computer, a server, or a network device, etc.) or a processor (processor) execute all or part of the steps of the methods in various embodiments of the present application.
  • the aforementioned storage media include: U disk, mobile hard disk, read-only memory (ROM, Read-Only Memory), random access memory (RAM, Random Access Memory), magnetic disk or optical disc, etc., which can store program codes. .

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Abstract

本申请公开了一种获得电荷参数的方法、分子力学模拟结果的方法及装置，所述获得电荷参数的方法包括：获得目标分子的初始静电势电荷；基于目标分子和多个环境分子构建模拟系统；利用初始静电势电荷对模拟系统进行分子动力学模拟，以至少获得多个时刻下的环境分子的坐标信息；基于多个时刻下的环境分子的坐标信息以及环境分子中各个原子的电荷量获得目标分子的第一静电势电荷；判断第一静电势电荷与初始静电势电荷是否符合第一预设条件；若是，将第一静电势电荷作为目标分子被环境分子环绕时的电荷参数。通过上述方式，本申请能够通过考虑溶剂分子所处的环境来拟合获得电荷参数，以提升溶剂分子在所处环境中分子力学模拟结果的精确度。

Description

获得电荷参数的方法、分子力学模拟结果的方法及装置 技术领域
本申请属于分子模拟技术领域，具体涉及一种获得电荷参数的方法、分子力学模拟结果的方法及装置。
背景技术
建立于经典力学基础上的分子力学以其速度优势在很多领域有着广泛的应用，例如，药物设计和材料设计领域。分子力场是分子力学中不可或缺的组成部分，分子力场中参数的好坏直接决定分子力学模拟结果的精度。传统的分子力场中包含成键项(例如，键长、键角、二面角等)和非键项(例如，电荷作用、范德华作用等)等。在非共价药物分子和蛋白质分子结合的过程中，非键项尤其是电荷作用起至关重要的作用。
而分子力场计算电荷作用需要力场中的电荷参数，且目前普遍采用点电荷模型来计算获得电荷参数。现在一般点电荷获得的方式是基于气相，也就是单个分子在孤立的环境中拟合量子化学方法产生的空间电势获得。但是在真实的生物应用场景中，所需要模拟的过程常常在溶液(一般是水)或蛋白环境中。这些环境会影响小分子本身的电势分布，从而造成和气相中不同的空间电势。即在气相中拟合获得的电荷参数可能会在实际的复杂环境中带来不精确的结果。
发明内容
本申请提供一种获得电荷参数的方法、分子力学模拟结果的方法及装置，通过考虑溶质分子所处的环境来拟合获得电荷参数，以提升溶质分子在所处环境中分子力学模拟结果的精确度。
为解决上述技术问题，本申请采用的一个技术方案是：提供一种获得电荷参数的方法，包括：S1、对溶质分子进行结构优化以获得至少一个目标分子，并获得每个所述目标分子的初始静电势电荷；S2、针对每个所述目标分子，基于所述目标分子和多个环境分子构建模拟系统；其中，所述目标分子被多个所述环境分子环绕；S3、利用所述初始静电势电荷对所述模拟系统进行分子动力学模拟，以至少获得模拟过程中多个时刻下的所述环境分子的坐标信息；S4、基 于多个时刻下的所述环境分子的坐标信息以及所述环境分子中各个原子的电荷量获得所述目标分子的第一静电势电荷；S5、判断所述第一静电势电荷与所述初始静电势电荷是否符合第一预设条件；S6、若是，将所述第一静电势电荷作为所述目标分子被所述环境分子环绕时的电荷参数；S7、否则，将所述第一静电势电荷作为所述初始静电势电荷并返回至步骤S3。
为解决上述技术问题，本申请采用的另一个技术方案是：提供一种获得分子力学模拟结果的方法，包括：利用上述任一实施例中所述的方法获得溶质分子的电荷参数；基于所述电荷参数获得所述溶质分子和所述环境分子的分子力学模拟结果。
为解决上述技术问题，本申请采用的另一个技术方案是：提供一种获得电荷参数的装置，包括：第一获得模块，用于对溶质分子进行结构优化以获得至少一个所述目标分子，并获得每个所述目标分子的初始静电势电荷；构建模块，与所述第一获得模块连接，用于针对每个所述目标分子，基于所述目标分子和多个环境分子构建模拟系统；其中，所述目标分子被多个所述环境分子环绕；第二获得模块，与所述构建模块连接，用于利用所述初始静电势电荷对所述模拟系统进行分子动力学模拟，以至少获得模拟过程中多个时刻下的所述环境分子的坐标信息；第三获得模块，与所述第二获得模块连接，用于基于多个时刻下的所述环境分子的坐标信息以及所述环境分子中各个原子的电荷量获得所述目标分子的第一静电势电荷；判断模块，与所述第三获得模块连接，用于判断所述第一静电势电荷与所述初始静电势电荷是否符合第一预设条件；执行模块，与所述判断模块连接，用于在所述判断模块判断为是时，将所述第一静电势电荷作为所述目标分子被所述环境分子环绕时的电荷参数；以及用于在所述判断模块判断为否时，将所述第一静电势电荷作为所述初始静电势电荷并返回至所述利用所述初始静电势电荷对所述模拟系统进行分子动力学模拟的步骤。
为解决上述技术问题，本申请采用的另一个技术方案是：提供一种电子设备，包括相互耦接的存储器和处理器，所述存储器中存储有程序指令，所述处理器用于执行所述程序指令以实现上述任一实施例中所述的获得电荷参数的方法，或所述的获得分子力学模拟结果的方法。
为解决上述技术问题，本申请采用的另一个技术方案是：提供一种存储装置，存储有能够被处理器运行的程序指令，所述处理器用于执行所述程序指令以实现上述任一实施例中所述的获得电荷参数的方法，或所述的获得分子力学模拟 结果的方法。
区别于现有技术情况，本申请的有益效果是：本申请获得电荷参数的方法的过程包括：对溶质分子进行结构优化以获得至少一个目标分子，并获得每个所述目标分子的初始静电势电荷；针对每个所述目标分子，基于所述目标分子和多个环境分子构建模拟系统；其中，所述目标分子被多个所述环境分子环绕；利用所述初始静电势电荷对所述模拟系统进行分子动力学模拟，以至少获得模拟过程中多个时刻下的所述环境分子的坐标信息；基于多个时刻下的所述环境分子的坐标信息以及所述环境分子中各个原子的电荷量获得所述目标分子的第一静电势电荷；判断所述第一静电势电荷与所述初始静电势电荷是否符合第一预设条件；若是，将所述第一静电势电荷作为所述目标分子被所述环境分子环绕时的电荷参数；否则，将所述第一静电势电荷作为所述初始静电势电荷并返回至所述利用所述初始静电势电荷对所述模拟系统进行分子动力学模拟的步骤。通过上述方式，本申请通过考虑环境分子对溶质分子的电荷参数的影响，以提升溶质分子在所处环境中分子力学模拟结果的精确度。
【附图说明】
为了更清楚地说明本申请实施例中的技术方案，下面将对实施例描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图，其中：
图1为本申请获得电荷参数的方法一实施方式的流程示意图；
图2为图1中步骤S1中对溶质分子进行结构优化以获得至少一个目标分子的一实施方式的流程示意图；
图3为图1中步骤S1中对溶质分子进行结构优化以获得至少一个目标分子的一实施方式的流程示意图；
图4为图1中步骤S3对应的一实施方式的流程示意图；
图5为图1中步骤S4对应的一实施方式的流程示意图；
图6为本申请获得分子力学模拟结果的方法一实施方式的流程示意图；
图7为本申请获得电荷参数的装置一实施方式的结构示意图；
图8为本申请电子设备一实施方式的结构示意图；
图9为本申请存储装置一实施方式的结构示意图。
【具体实施方式】
下面将结合本申请实施例中的附图，对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，均属于本申请保护的范围。
请参阅图1，图1为本申请获得电荷参数的方法一实施方式的流程示意图，该方法包括：
S1：对溶质分子进行结构优化以获得至少一个目标分子，并获得每个目标分子的初始静电势电荷。
具体地，在一个实施方式中，请参阅图2，图2为图1中步骤S1中对溶质分子进行结构优化以获得至少一个目标分子的一实施方式的流程示意图。上述步骤S1中对溶质分子进行结构优化以获得至少一个目标分子的过程具体包括：
S201：基于多个环境分子构建隐式溶剂模型。
可选地，环境分子可以包括有机溶剂分子或无机溶剂分子或蛋白质分子等；其中，有机溶剂分子包括甲醇、乙醇、苯、乙醚、二氯甲烷、丙酮、四氢呋喃、乙酸乙酯、乙腈或甲苯等；无机溶剂分子包括水、氨、氟化氢、或二氧化硫等。上述仅仅只是列举了几种比较常见的溶剂分子，在其他实施例中，可以根据实际应用场景选择对应的环境分子；且在实际应用场景中环境分子一般择一引用，即环境分子可以为上述所列举的分子中一个。另一可选地，上述隐式溶剂模型可以为Onsager(昂萨格模型)、PCM(Polarizable continuum model，极性连续介质模型)、CPCM(conductor-like polarizable continuum model，导体极性连续介质模型)、IPCM(isodensity polarizable continuum model，等密度极性连续介质模型)、SCIPCM(self-consistent isodensity polarizable continuum model，自洽等密度极性连续介质模型)、COSMO(conductor-like screening model，类导体遮蔽模型)、SMD(solvation model based on density，基于密度的溶剂模型)等。
简单来说，隐式溶剂模型是将溶剂分子(即环境分子)当成一种连续介质的模型，即就是不具体描述溶质分子附近的环境分子的具体结构和分布，而是把周围环境简单地当成可极化的连续介质来考虑的。这种考虑溶剂效应的好处是可以表现溶剂的平均效应而不需要像显式溶剂模型那样需要考虑各种可能的溶剂层分子的排布方式，而且不至于令计算耗时增加很高。
S202：将溶质分子放置于隐式溶剂模型中进行结构优化，获得局部能量最低的目标分子。
可选地，可以利用开源的量子化学计算软件(如，NWChem、GAMESS、Gaussian等)中的Hartree-Fock(HF，哈特里-福克)方法进行结构优化，以获得局部能量最低的目标分子。以NWChem软件为例，在操作NWChem软件时可以直接选取关键词“task hf energy”即可获得目标分子。
进一步，在获得目标分子之后，还可以利用当前的量子化学计算软件获得目标分子的初始静电势(ESP)电荷Q0、以及目标分子中各个原子的坐标。以NWChem软件为例，在操作NWChem软件时可以直接选取关键词“task esp”即可获得目标分子的初始静电势电荷Q0。
在又一个实施方式中，当溶质分子的分子结构较大时，其可能包括多种构象，此时可以针对不同的构象获得对应的目标分子，以提高后续获得的溶质分子的电荷参数的精确度。具体而言，请参阅图3，图3为图1中步骤S1中对溶质分子进行结构优化以获得至少一个目标分子的一实施方式的流程示意图。上述步骤S1中对溶质分子进行结构优化以获得至少一个目标分子的过程具体包括：
S301：对溶质分子进行二面角旋转以获得多个不同的构象分子。
具体地，由公知常识可知，构象的改变不涉及共价键的改变，不同的构象分子的差异仅仅在于立体结构上的不同。
S302：对每个构象分子进行结构优化以获得对应的优化结构分子。
具体地，上述步骤S302的实现过程可以为：首先，基于多个环境分子构建隐式溶剂模型；该步骤与上述步骤S201类似，在此不再详述。接着，将构象分子放置于隐式溶剂模型中进行结构优化，获得局部能量最低的目标分子；该步骤与上述步骤S202类似，在此不再详述。
S303：将所有优化结构分子中的相同立体结构分子进行合并，以获得至少一个目标分子。
可选地，所有构象分子对应的优化结构分子的立体结构可能都相同，此时经过合并最终获得的目标分子的个数为一。例如，溶质分子A进行二面角旋转后形成的构象分子包括A、A1、A2、A3，构象分子A、A1、A2、A3对应的优化结构分子均为B，则此时目标分子为B。
或者，所有构象分子对应的优化结构分子的立体结构可能包括至少两种， 此时经过合并最终获得的目标分子的个数为至少两种。例如，溶质分子A进行二面角旋转后形成的构象分子包括A、A1、A2、A3，构象分子A、A1对应的优化结构分子均为B，构象分子A2、A3对应的优化结构分子均为B1，则此时目标分子为B和B1。
S2：针对每个目标分子，基于目标分子和多个环境分子构建模拟系统；其中，目标分子被多个环境分子环绕。
具体地，在一个实施方式中，上述步骤S2中基于目标分子和多个环境分子构建模拟系统的步骤包括：基于多个环境分子构建显式溶剂模型；将目标分子放置于显式溶剂模型中，获得模拟系统。可选地，上述显式溶剂模型可以为TIP3P(transferable intermolecular potential 3 point，可迁移的分子间势的3点模型)、TIP4P(transferable intermolecular potential 4 point，可迁移的分子间势的4点模型)、TIP5P(transferable intermolecular potential 5 point，可迁移的分子间势的5点模型)等。显式溶剂模型是将每个溶剂分子(即环境分子)作为单独的分子进行模拟的模型；即显式溶剂模型中每个环境分子都是一个单独的分子，利用显式溶剂模型可以考虑环境分子中每个原子对溶质分子的电荷参数的影响，以提高后续获得的电荷参数的准确性。
S3：利用初始静电势电荷对模拟系统进行分子动力学模拟，以至少获得模拟过程中多个时刻下的环境分子的坐标信息。
具体地，请参阅图4，图4为图1中步骤S3对应的一实施方式的流程示意图，上述步骤S3具体包括：
S401：利用初始静电势电荷初始化分子动力学模型。
具体地，可以利用分子动力学软件GROMACS中内置的动力学模型进行动力学模拟；且此时动力学模型中的电荷参数为初始静电势电荷Q0。
S402：基于初始化后的分子动力学模型对模拟系统进行动力学模拟，且在模拟过程中保持目标分子中各个原子的坐标不变，仅允许环境分子的各个原子的坐标改变。
可选地，在本实施例中，目标分子中各个原子的坐标可以与经过步骤S1中获得的目标分子的坐标相同；即可以保持步骤S1和步骤S3中目标分子的位置不变。
S403：在预定模拟时间范围内，每间隔预定时间间隔保存当前时刻下所有环境分子中各个原子的坐标。
可选地，预定模拟时间范围可以为2纳秒，预定时间间隔可以为10皮秒，此时可以获得200个时刻下所有环境分子中各个原子的坐标。
上述保持目标分子中各个原子坐标不变的方式可以使得后续步骤S4中获得第一静电势电荷的方式较为简单，且计算量较小。
S4：基于多个时刻下的环境分子的坐标信息以及环境分子中各个原子的电荷量获得目标分子的第一静电势电荷。
可选地，当步骤S3中保持目标分子的各个原子的坐标不变时，请参阅图5，图5为图1中步骤S4对应的一实施方式的流程示意图。上述步骤S4具体包括：
S501：将各个时刻下的所有环境分子中各个原子的坐标作为目标分子外部的多个点电荷的坐标，且将各个时刻下的所有环境分子中各个原子的电荷量与多个时刻的个数的第二比值作为对应位置处的点电荷的电荷量。
例如，当前溶质分子外围有100个环境分子，环境分子中每个原子的电荷量可以相同或不同。例如，当环境分子为水分子时，每个水分子有3个原子，水分子中氧原子的电荷量为-0.8，水分子中氢原子的电荷量为0.4。那么同一时刻下当前环境中有3*100个点电荷。当步骤S3中获得200个时刻下的环境分子坐标时，则当前溶剂分子外围共用300*200＝60000个点电荷，每个点电荷位置处的电荷量为该点电荷坐标处对应的原子的电荷量除以200。
S502：基于目标分子外部的多个点电荷的坐标及其电荷量拟合获得第一静电势电荷。
可选地，可以通过量子化学HF方法的单点能(single point energy)计算并拟合得到第一静电势电荷Q1。
另一可选地，当步骤S3中动力学模拟过程中目标分子的位置也发生移动时，则此时可以先将多个时刻下的模拟系统的位置进行移动，此时模拟系统中的目标分子和环境分子会同步移动。当各个时刻下的目标分子的位置相同时，进入步骤S501。
S5：判断第一静电势电荷与初始静电势电荷是否符合第一预设条件。
具体地，上述步骤S5的具体实现过程可以为：判断第一静电势电荷Q1与初始静电势电荷Q0之间的平均方差是否小于阈值；可选地，该阈值可以为0.01等。该设计方式计算量较小。
当然，在其他实施例中，上述步骤S5的具体实现过程也可为：判断第一静电势电荷Q1与初始静电势电荷Q0之间的标准差是否小于阈值，本申请对此不 作限定。
S6：若是，将第一静电势电荷作为目标分子被环境分子环绕时的电荷参数。
S7：否则，将第一静电势电荷作为初始静电势电荷，并返回至步骤S3。
在上述设计方式中，通过考虑环境分子对溶质分子的电荷参数的影响，以提升溶质分子在所处环境中分子力学模拟结果的精确度。此外，一般而言，隐式溶剂模型计算速率较快，但准确率相比与显式溶剂模型差一些；显式溶剂模型比隐式溶剂模型在考虑溶质分子和溶剂分子之间的相互作用力时具有更高的精度，但是会消耗更多的计算资源，计算效率较慢。本申请中在步骤S1中先利用计算速率快但准确率没有这么高的隐式溶剂模型进行计算，然后再利用计算速率慢但准确率高的显式溶剂模型进行计算，能够提高整个方法的效果，包括效率和准确度。
此外，当步骤S1中获得的目标分子的个数为至少两个时，上述步骤S7之后，还可以包括：获得所有目标分子对应的电荷参数的和值；将和值与目标分子的个数的第一比值作为溶质分子被环境分子环绕时的电荷参数。该设计方式可以进一步提高溶质分子的电荷参数的精确度。
请参阅图6，图6为本申请获得分子力学模拟结果的方法一实施方式的流程示意图，上述方法具体包括：
S601：获得溶质分子的电荷参数。
可选地，在本实施例中，上述步骤S601的实现过程可参见上述任一实施例中所提及的获得电荷参数的方法。
S602：基于电荷参数获得溶质分子和环境分子的分子力学模拟结果。
在一个应用场景中，当利用步骤S601中所获得电荷参数计算一些与溶剂化相关的性质如水合自由能(即分子从气相溶解于水中所需的自由能)时，以所获得的第一结果；相比利用气相方法获得的电荷参数计算获得的第二结果而言，第一结果相比第二结果更接近实验值。
例如，将本申请所提供的获得电荷参数的方法应用于Freesolv数据集中，将力场中的电荷参数(AM1-BCC模型产生)替换为经过图1中的流程产生的考虑水环境的电荷参数，而保留力场中其他参数，最后水合自由能计算值和实验值的平均方差为1.12kcal/mol。当电荷参数采用气相方法获得时，所计算获得的水合自由能与实验值的平均方差为1.51kcal/mol。较小的方差说明计算值和实验值更加符合，本申请所提供的新的电荷参数获得流程带来更精确的计算值。
请参阅图7，图7为本申请获得电荷参数的装置一实施方式的结构示意图，上述获得电荷参数的装置包括第一获得模块10、构建模块12、第二获得模块14、第三获得模块16、判断模块18和执行模块11。
其中，第一获得模块10用于对溶质分子进行结构优化以获得至少一个目标分子，并获得每个目标分子的初始静电势电荷。构建模块12与第一获得模块10连接，用于针对每个目标分子，基于目标分子和多个环境分子构建模拟系统；其中，目标分子被多个环境分子环绕。第二获得模块14与构建模块12连接，用于利用初始静电势电荷对模拟系统进行分子动力学模拟，以至少获得模拟过程中多个时刻下的环境分子的坐标信息。第三获得模块16与第二获得模块14连接，用于基于多个时刻下的环境分子的坐标信息以及环境分子中各个原子的电荷量获得目标分子的第一静电势电荷。判断模块18与第三获得模块16连接，用于判断第一静电势电荷与初始静电势电荷是否符合第一预设条件。执行模块11与判断模块18连接，用于在判断模块判断为是时，将第一静电势电荷作为目标分子被环境分子环绕时的电荷参数；以及用于在判断模块判断为否时，将第一静电势电荷作为初始静电势电荷并返回至利用初始静电势电荷对模拟系统进行分子动力学模拟的步骤。
可选地，上述第一获得模块10具体用于基于多个环境分子构建隐式溶剂模型；将溶质分子放置于隐式溶剂模型中进行结构优化，获得局部能量最低的目标分子。或者，第一获得模块10具体用于对溶质分子进行二面角旋转以获得多个不同的构象分子；对每个构象分子进行结构优化以获得对应的优化结构分子；将所有优化结构分子中的相同立体结构分子进行合并，以获得至少一个目标分子。
另一可选地，上述构建模块12具体用于基于多个环境分子构建显式溶剂模型；将目标分子放置于显式溶剂模型中，获得模拟系统。
另一可选地，上述第二获得模块14具体用于利用初始静电势电荷初始化分子动力学模型；基于初始化后的分子动力学模型对模拟系统进行动力学模拟，且在模拟过程中保持目标分子中各个原子的坐标不变，仅允许环境分子的各个原子的坐标改变；在预定模拟时间范围内，每间隔预定时间间隔保存当前时刻下所有环境分子中各个原子的坐标。
另一可选地，上述第三获得模块16具体用于将各个时刻下的所有环境分子中各个原子的坐标作为目标分子外部的多个点电荷的坐标，且将各个时刻下的 所有环境分子中各个原子的电荷量与多个时刻的个数的第二比值作为对应位置处的点电荷的电荷量；基于目标分子外部的多个点电荷的坐标及其电荷量拟合获得第一静电势电荷。
另一可选地，上述判断模块18具体用于判断第一静电势电荷与初始静电势电荷之间的平均方差是否小于阈值。
此外，当目标分子的个数为至少两个时，上述装置还可以包括第四获得模块，与执行模块18连接，用于获得所有目标分子对应的电荷参数的和值；将和值与目标分子的个数的第一比值作为溶质分子被环境分子环绕时的电荷参数。
请参阅图8，图8为本申请电子设备一实施方式的结构示意图，该电子设备包括：相互耦接的存储器22和处理器20，存储器22中存储有程序指令，处理器20用于执行程序指令以实现上述任一获得电荷参数的方法，或获得分子力学模拟结果的方法。具体地，电子设备包括但不限于：台式计算机、笔记本电脑、平板电脑、服务器等，在此不做限定。此外，处理器20还可以称为CPU(Center Processing Unit,中央处理单元)。处理器20可能是一种集成电路芯片，具有信号处理能力。处理器20还可以是、通用处理器、数字信号处理器(Digital Signal Processor，DSP)、专用集成电路(Application Specific Integrated Circuit,ASIC)、现场可编程门阵列(Field-Programmable Gate Array,FPGA)或者其他可编程逻辑器件、分立门或者晶体管逻辑器件、分立硬件组件。通用处理器可以是微处理器或者该处理器也可以是任何常规的处理器等。另外，处理器20可以由集成电路芯片共同实现。
请参阅图9，图9为本申请存储装置一实施方式的结构示意图，该存储装置30存储有能够被处理器运行的程序指令300，程序指令300用于实现上述任一获得电荷参数的方法，或获得分子力学模拟结果的方法。
在本申请所提供的几个实施例中，应该理解到，所揭露的方法和装置，可以通过其它的方式实现。例如，以上所描述的装置实施方式仅仅是示意性的，例如，模块或单元的划分，仅仅为一种逻辑功能划分，实际实现时可以有另外的划分方式，例如多个单元或组件可以结合或者可以集成到另一个系统，或一些特征可以忽略，或不执行。另一点，所显示或讨论的相互之间的耦合或直接耦合或通信连接可以是通过一些接口，装置或单元的间接耦合或通信连接，可以是电性、机械或其它的形式。
作为分离部件说明的单元可以是或者也可以不是物理上分开的，作为单元 显示的部件可以是或者也可以不是物理单元，即可以位于一个地方，或者也可以分布到多个网络单元上。可以根据实际的需要选择其中的部分或者全部单元来实现本实施方式方案的目的。
另外，在本申请各个实施例中的各功能单元可以集成在一个处理单元中，也可以是各个单元单独物理存在，也可以两个或两个以上单元集成在一个单元中。上述集成的单元既可以采用硬件的形式实现，也可以采用软件功能单元的形式实现。
集成的单元如果以软件功能单元的形式实现并作为独立的产品销售或使用时，可以存储在一个计算机可读取存储介质中。基于这样的理解，本申请的技术方案本质上或者说对现有技术做出贡献的部分或者该技术方案的全部或部分可以以软件产品的形式体现出来，该计算机软件产品存储在一个存储介质中，包括若干指令用以使得一台计算机设备(可以是个人计算机，服务器，或者网络设备等)或处理器(processor)执行本申请各个实施方式方法的全部或部分步骤。而前述的存储介质包括：U盘、移动硬盘、只读存储器(ROM，Read-Only Memory)、随机存取存储器(RAM，Random Access Memory)、磁碟或者光盘等各种可以存储程序代码的介质。
以上所述仅为本申请的实施例，并非因此限制本申请的专利范围，凡是利用本申请说明书及附图内容所作的等效结构或等效流程变换，或直接或间接运用在其它相关的技术领域，均同理包括在本申请的专利保护范围内。

Claims (20)

  1. 一种获得电荷参数的方法，其特征在于，包括：
    S1、对溶质分子进行结构优化以获得至少一个目标分子，并获得每个所述目标分子的初始静电势电荷；
    S2、针对每个所述目标分子，基于所述目标分子和多个环境分子构建模拟系统；其中，所述目标分子被多个所述环境分子环绕；
    S3、利用所述初始静电势电荷对所述模拟系统进行分子动力学模拟，以至少获得模拟过程中多个时刻下的所述环境分子的坐标信息；
    S4、基于多个时刻下的所述环境分子的坐标信息以及所述环境分子中各个原子的电荷量获得所述目标分子的第一静电势电荷；
    S5、判断所述第一静电势电荷与所述初始静电势电荷是否符合第一预设条件；
    S6、若是，将所述第一静电势电荷作为所述目标分子被所述环境分子环绕时的电荷参数；
    S7、否则，将所述第一静电势电荷作为所述初始静电势电荷，并返回至步骤S3。
  2. 根据权利要求1所述的方法，其特征在于，所述对溶质分子进行结构优化以获得至少一个目标分子的步骤，包括：
    基于多个所述环境分子构建隐式溶剂模型；
    将所述溶质分子放置于所述隐式溶剂模型中进行结构优化，获得局部能量最低的所述目标分子。
  3. 根据权利要求1所述的方法，其特征在于，所述对溶质分子进行结构优化以获得至少一个目标分子的步骤，包括：
    对所述溶质分子进行二面角旋转以获得多个不同的构象分子；
    对每个所述构象分子进行结构优化以获得对应的优化结构分子；
    将所有所述优化结构分子中的相同立体结构分子进行合并，以获得至少一个所述目标分子。
  4. 根据权利要求3所述的方法，其特征在于，所述目标分子的个数为至少两个，所述方法还包括：
    获得所有所述目标分子对应的所述电荷参数的和值；
    将所述和值与所述目标分子的个数的第一比值作为所述溶质分子被所述环 境分子环绕时的电荷参数。
  5. 根据权利要求1所述的方法，其特征在于，所述基于所述目标分子和多个环境分子构建模拟系统的步骤，包括：
    基于多个所述环境分子构建显式溶剂模型；
    将所述目标分子放置于所述显式溶剂模型中，获得模拟系统。
  6. 根据权利要求1所述的方法，其特征在于，所述利用所述初始静电势电荷对所述模拟系统进行分子动力学模拟，以至少获得模拟过程中多个时刻下的所述环境分子的坐标信息的步骤，包括：
    利用所述初始静电势电荷初始化分子动力学模型；
    基于初始化后的所述分子动力学模型对所述模拟系统进行动力学模拟，且在模拟过程中保持所述目标分子中各个原子的坐标不变，仅允许所述环境分子的各个原子的坐标改变；
    在预定模拟时间范围内，每间隔预定时间间隔保存当前时刻下所有所述环境分子中各个原子的坐标。
  7. 根据权利要求6所述的方法，其特征在于，所述基于多个时刻下的所述环境分子的坐标信息以及所述环境分子中各个原子的电荷量获得所述目标分子的第一静电势电荷的步骤，包括：
    将各个时刻下的所有所述环境分子中各个原子的坐标作为所述目标分子外部的多个点电荷的坐标，且将各个时刻下的所有所述环境分子中各个原子的电荷量与所述多个时刻的个数的第二比值作为对应位置处的所述点电荷的电荷量；
    基于所述目标分子外部的多个所述点电荷的坐标及其电荷量拟合获得所述第一静电势电荷。
  8. 根据权利要求1所述的方法，其特征在于，所述判断所述第一静电势电荷与所述初始静电势电荷是否符合第一预设条件的步骤，包括：
    判断所述第一静电势电荷与所述初始静电势电荷之间的平均方差是否小于阈值。
  9. 根据权利要求1所述的方法，其特征在于，
    所述环境分子包括有机溶剂分子或无机溶剂分子或蛋白质分子；其中，所述有机溶剂分子包括甲醇、乙醇、苯、乙醚、二氯甲烷、丙酮、四氢呋喃、乙酸乙酯、乙腈或甲苯；所述无机溶剂分子包括水、氨、氟化氢、或二氧化硫。
  10. 一种获得分子力学模拟结果的方法，其特征在于，包括：
    利用权利要求1-9中任一项所述的方法获得溶质分子的电荷参数；
    基于所述电荷参数获得所述溶质分子和所述环境分子的分子力学模拟结果。
  11. 一种获得电荷参数的装置，其特征在于，包括：
    第一获得模块，用于对溶质分子进行结构优化以获得至少一个所述目标分子，并获得每个所述目标分子的初始静电势电荷；
    构建模块，与所述第一获得模块连接，用于针对每个所述目标分子，基于所述目标分子和多个环境分子构建模拟系统；其中，所述目标分子被多个所述环境分子环绕；
    第二获得模块，与所述构建模块连接，用于利用所述初始静电势电荷对所述模拟系统进行分子动力学模拟，以至少获得模拟过程中多个时刻下的所述环境分子的坐标信息；
    第三获得模块，与所述第二获得模块连接，用于基于多个时刻下的所述环境分子的坐标信息以及所述环境分子中各个原子的电荷量获得所述目标分子的第一静电势电荷；
    判断模块，与所述第三获得模块连接，用于判断所述第一静电势电荷与所述初始静电势电荷是否符合第一预设条件；
    执行模块，与所述判断模块连接，用于在所述判断模块判断为是时，将所述第一静电势电荷作为所述目标分子被所述环境分子环绕时的电荷参数；以及用于在所述判断模块判断为否时，将所述第一静电势电荷作为所述初始静电势电荷并返回至所述利用所述初始静电势电荷对所述模拟系统进行分子动力学模拟的步骤。
  12. 根据权利要求11所述的装置，其特征在于，
    所述第一获得模块用于基于多个所述环境分子构建隐式溶剂模型；将所述溶质分子放置于所述隐式溶剂模型中进行结构优化，获得局部能量最低的所述目标分子。
  13. 根据权利要求11所述的装置，其特征在于，
    所述第一获得模块用于对所述溶质分子进行二面角旋转以获得多个不同的构象分子；对每个所述构象分子进行结构优化以获得对应的优化结构分子；将所有所述优化结构分子中的相同立体结构分子进行合并，以获得至少一个所述 目标分子。
  14. 根据权利要求13所述的装置，其特征在于，所述目标分子的个数为至少两个，所述装置还包括：
    第四获得模块，与所述执行模块连接，用于获得所有所述目标分子对应的所述电荷参数的和值；将所述和值与所述目标分子的个数的第一比值作为所述溶质分子被所述环境分子环绕时的电荷参数。
  15. 根据权利要求11所述的装置，其特征在于，
    所述构建模块用于基于多个所述环境分子构建显式溶剂模型；将所述目标分子放置于所述显式溶剂模型中，获得模拟系统。
  16. 根据权利要求11所述的装置，其特征在于，
    所述第二获得模块用于利用所述初始静电势电荷初始化分子动力学模型；基于初始化后的所述分子动力学模型对所述模拟系统进行动力学模拟，且在模拟过程中保持所述目标分子中各个原子的坐标不变，仅允许所述环境分子的各个原子的坐标改变；在预定模拟时间范围内，每间隔预定时间间隔保存当前时刻下所有所述环境分子中各个原子的坐标。
  17. 根据权利要求16所述的装置，其特征在于，
    所述第三获得模块用于将各个时刻下的所有所述环境分子中各个原子的坐标作为所述目标分子外部的多个点电荷的坐标，且将各个时刻下的所有所述环境分子中各个原子的电荷量与所述多个时刻的个数的第二比值作为对应位置处的所述点电荷的电荷量；基于所述目标分子外部的多个所述点电荷的坐标及其电荷量拟合获得所述第一静电势电荷。
  18. 根据权利要求11所述的装置，其特征在于，
    所述判断模块用于判断所述第一静电势电荷与所述初始静电势电荷之间的平均方差是否小于阈值。
  19. 一种电子设备，其特征在于，包括相互耦接的存储器和处理器，所述存储器中存储有程序指令，所述处理器用于执行所述程序指令以实现权利要求1至9任一项所述的获得电荷参数的方法，或权利要求10中所述的获得分子力学模拟结果的方法。
  20. 一种存储装置，其特征在于，存储有能够被处理器运行的程序指令，所述处理器用于执行所述程序指令以实现权利要求1至9任一项所述的获得电荷参数的方法，或权利要求10中所述的获得分子力学模拟结果的方法。
PCT/CN2021/139227 2021-12-17 2021-12-17 获得电荷参数的方法、分子力学模拟结果的方法及装置 WO2023108622A1 (zh)

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