Protein automatic molecular dynamics simulation method and platform

Abstract

The invention relates to a protein automatic molecular dynamics simulation method and platform, and the method comprises the steps: obtaining a protein structure file, and carrying out the preprocessing of the protein structure file; obtaining a simulation system type selected by a user, and generating an independent topological file of an independent protein system corresponding to the simulation system type or a combined topological file of a composite system of protein and ligand based on the preprocessed protein structure file; adding a solvation box, a water model and ions to the generated independent topological file or the combined topological file to obtain a simulation system file; a molecular dynamics simulation type selected by a user is obtained, a simulation parameter file and an automatic script corresponding to the molecular dynamics simulation type are generated, and the molecular dynamics simulation type comprises conventional molecular dynamics simulation and molecular dynamics simulation applying enhanced sampling; and executing the automatic script to run corresponding molecular dynamics simulation based on the simulation system file and the simulation parameter file to obtain an output file.

Description

Technical Field

[0001] The present disclosure relates to the field of bio-computing technology, and in particular, to a method and platform for automated molecular dynamics simulation of proteins. Background Art

[0002] With the development of computer science and the increasing popularity of molecular dynamics (MD) simulation methods, MD simulation has become an important tool for studying the structure and dynamic behavior of biomolecules. This technology is widely used in fields such as drug design, protein folding, and molecular recognition. However, existing molecular dynamics simulation platforms still have many deficiencies in terms of operation complexity, user-friendliness, system compatibility, and support for enhanced sampling techniques.

[0003] Traditional molecular dynamics simulation tools (such as GROMACS, AMBER, NAMD, etc.) are powerful and can handle complex biological systems, but their operation processes often require users to have a deep professional background. Generally, users need to manually perform steps such as molecular modeling, force field selection, parameterization, condition setting, and data analysis. The whole process is cumbersome and error-prone. In addition, conventional molecular dynamics methods are prone to falling into local energy minima when exploring the free energy surface of the system, resulting in low sampling efficiency. Moreover, in conventional molecular dynamics simulations, the sampling space of the molecular system is limited. Especially when studying protein conformational changes or small molecule binding sites, it may take a long time to obtain sufficient sampling results. Summary of the Invention

[0004] The purpose of the present disclosure is to provide a method and platform for automated molecular dynamics simulation of proteins, aiming to provide an automated molecular dynamics simulation process for proteins to simplify the operation process, and to provide enhanced sampling options to improve the sampling rate and reduce the risk of the system falling into local energy minima.

[0005] To achieve the above object, in the first aspect of the present disclosure, a method for automated molecular dynamics simulation of proteins is provided. The method includes:

[0006] Obtain a protein structure file and preprocess the protein structure file;

[0007] Obtain the type of simulation system selected by the user, and generate an independent topology file for a separate protein system or a combined topology file for a protein-ligand complex system corresponding to the type of simulation system based on the preprocessed protein structure file;

[0008] Add a solvation box, a water model, and ions to the generated independent topology file or combined topology file to obtain a simulation system file;

[0009] Obtain the type of molecular dynamics simulation selected by the user, and generate a simulation parameter file and an automated script corresponding to the type of molecular dynamics simulation. The types of molecular dynamics simulation include conventional molecular dynamics simulation and molecular dynamics simulation applying enhanced sampling;

[0010] Execute the automated script to run the corresponding molecular dynamics simulation based on the simulation system file and the simulation parameter file, and obtain an output file.

[0011] Optionally, the preprocessing of the protein structure file includes:

[0012] Read the protein structure file. If there are unnecessary components in the protein structure file, remove the unnecessary components. If there are missing atoms or residues in the protein structure file, repair the missing atoms or residues.

[0013] Optionally, the obtaining of the type of simulation system selected by the user and generating an independent topology file for a separate protein system or a combined topology file for a protein-ligand complex system corresponding to the type of simulation system based on the preprocessed protein structure file includes:

[0014] Obtain the simulation system selection information of the user to determine whether the type of simulation system selected by the user is a protein-ligand complex system;

[0015] If it is determined that the selected type of simulation system is not a protein-ligand complex system, generate an independent topology file for a separate protein system based on the preprocessed protein structure file;

[0016] If it is determined that the selected type of simulation system is a protein-ligand complex system, obtain the ligand structure file provided by the user and perform preprocessing;

[0017] Judge whether there is a ligand parameter file provided by the user. If there is a ligand parameter file, directly obtain the ligand parameter file; if there is no ligand parameter file, automatically generate a ligand parameter file based on the preset force field;

[0018] Judge whether there is a binding position of the protein and the ligand specified by the user. If there is such a binding position, based on the binding position and the ligand parameter file, combine the preprocessed protein structure file and the preprocessed ligand structure file to form a protein-ligand complex system, and generate a combined topology file for the protein-ligand complex system; if there is no such binding position, automatically use a molecular docking tool to generate the best binding site of the protein and the ligand, and based on the binding site and the ligand parameter file, combine the preprocessed protein structure file and the preprocessed ligand structure file to form a protein-ligand complex system, and generate a combined topology file for the protein-ligand complex system.

[0019] Optionally, obtaining the type of molecular dynamics simulation selected by the user and generating a simulation parameter file and an automation script corresponding to the type of molecular dynamics simulation includes:

[0020] Obtaining the simulation type selection information of the user to determine whether the user applies enhanced sampling;

[0021] If it is determined not to apply enhanced sampling, generating a simulation parameter file and an automation script for conventional molecular dynamics simulation;

[0022] If it is determined to apply enhanced sampling, generating a simulation parameter file and an automation script for molecular dynamics simulation with enhanced sampling applied.

[0023] Optionally, the automation script for the conventional molecular dynamics simulation includes the following simulation calculation steps:

[0024] Performing energy minimization on the individual protein system or composite system of the simulation system file to optimize the atomic positions in the simulation system file and eliminate the high-energy superposition in the corresponding structure of the simulation system file;

[0025] Gradually heating the corresponding system of the simulation system file to the target temperature and maintaining a constant temperature;

[0026] Controlling the pressure of the corresponding system of the simulation system file through the NPT ensemble to ensure reaching an equilibrium state;

[0027] Running a production simulation in the equilibrium state to generate an output file, which includes a trajectory file and an energy file.

[0028] Optionally, the automation script for the molecular dynamics simulation with enhanced sampling applied includes the following simulation calculation steps of creating multiple replicas and running based on the REST2 enhanced sampling algorithm:

[0029] Performing energy minimization on the individual protein system or composite system of the simulation system file to optimize the atomic positions in the simulation system file and eliminate the high-energy superposition in the corresponding structure of the simulation system file;

[0030] Gradually heating the corresponding system of the simulation system file to the target temperature and maintaining a constant temperature

[0031] Controlling the pressure of the corresponding system of the simulation system file through the NPT ensemble to ensure reaching an equilibrium state;

[0032] Running a production simulation in the equilibrium state to generate an output file, which includes a trajectory file and an energy file.

[0033] Optionally, the method further includes:

[0034] Perform result analysis based on the output file.

[0035] In a second aspect of the present disclosure, there is provided an automated protein molecular dynamics simulation platform, which includes:

[0036] A preprocessing module, configured to obtain a protein structure file and preprocess the protein structure file;

[0037] A generation module, configured to obtain the type of simulation system selected by the user, and generate an independent topology file for a separate protein system corresponding to the type of simulation system or a combined topology file for a protein-ligand complex system based on the preprocessed protein structure file;

[0038] An addition module, configured to add a solvation box, a water model, and ions to the generated independent topology file or the combined topology file to obtain a simulation system file;

[0039] A script module, configured to obtain the type of molecular dynamics simulation selected by the user, and generate a simulation parameter file and an automated script corresponding to the type of molecular dynamics simulation, where the type of molecular dynamics simulation includes conventional molecular dynamics simulation and molecular dynamics simulation applying enhanced sampling;

[0040] A calculation module, configured to execute the automated script to run the corresponding molecular dynamics simulation based on the simulation system file and the simulation parameter file to obtain an output file.

[0041] In a third aspect of the present disclosure, there is provided a computer-readable storage medium, on which a computer program is stored, and when the program is executed by a processor, the steps of the method described in any one of the first aspects above are implemented.

[0042] In a fourth aspect of the present disclosure, there is provided an electronic device, including:

[0043] A memory, on which a computer program is stored;

[0044] A processor, configured to execute the computer program in the memory to implement the steps of the method described in any one of the first aspects above.

[0045] Through the above technical solution, the obtained protein structure file can be automatically preprocessed, and based on this, an independent topology file for a separate protein system or a combined topology file for a protein-ligand complex system can be generated. A solvation box, a water model, and ions are added to the topology file to obtain a simulation system file as the input for molecular dynamics simulation. According to the user's selection, an automated script for conventional molecular dynamics simulation or molecular dynamics simulation applying enhanced sampling and a simulation parameter file required for the simulation are automatically generated. Running the automated script can execute the corresponding molecular dynamics simulation to obtain an output file containing the running results. This process does not require manual setting of complex parameters, does not require manual invocation of quantum chemistry tools or writing of scripts, realizes the full automation of molecular dynamics simulation, simplifies the operation process, reduces the risk of errors, and improves efficiency and accuracy. The provided enhanced sampling option can reduce the risk of the system falling into local energy minima and make the exploration of the free energy surface more efficient.

[0046] Other features and advantages of the present disclosure will be described in detail in the subsequent specific implementation section. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The drawings are used to provide a further understanding of the present disclosure and constitute a part of the specification. Together with the following specific implementation, they are used to explain the present disclosure, but do not constitute a limitation to the present disclosure. In the drawings:

[0048] Figure 1 is a flowchart of a protein automated molecular dynamics simulation method shown according to an exemplary embodiment.

[0049] Figure 2 is another flowchart of a protein automated molecular dynamics simulation method shown according to an exemplary embodiment.

[0050] Figure 3 is a flowchart of step S102 in a protein automated molecular dynamics simulation method shown according to an exemplary embodiment.

[0051] Figure 4 is another flowchart of a protein automated molecular dynamics simulation method shown according to an exemplary embodiment.

[0052] Figure 5 is a statistical chart of the root mean square deviation in the simulation process of the 4YAY protein shown according to an exemplary embodiment.

[0053] Figure 6 is a statistical chart of the root mean square fluctuation in the simulation process of the 4YAY protein shown according to an exemplary embodiment.

[0054] Figure 7It is a statistical graph of the radius of gyration during the 4YAY protein simulation shown according to an exemplary embodiment.

[0055] Figure 8 It is a statistical graph of the shortest contact distance between protein residues and small molecules in the 7JMT complex system shown according to an exemplary embodiment.

[0056] Figure 9 It is a statistical graph of the information of the MMPBSA binding energy of protein residues and small molecules in the 7JMT complex system with respect to energy terms shown according to an exemplary embodiment.

[0057] Figure 10 It is a statistical graph of the information of the MMPBSA binding energy of protein residues and small molecules in the 7JMT complex system with respect to residues shown according to an exemplary embodiment

[0058] Figure 11 It is a free energy landscape diagram of the protein in the 7JMT complex system shown according to an exemplary embodiment.

[0059] Figure 12 It is a block diagram of a protein automated molecular dynamics simulation platform shown according to an exemplary embodiment.

[0060] Figure 13 It is a block diagram of an electronic device shown according to an exemplary embodiment. Detailed implementation manners

[0061] The following will describe the detailed implementation manners of the present disclosure in conjunction with the accompanying drawings. It should be understood that the detailed implementation manners described herein are only for explaining and interpreting the present disclosure, and are not used to limit the present disclosure.

[0062] Traditional molecular dynamics simulation tools have many deficiencies in performing molecular dynamics simulations on biological systems, including the following aspects:

[0063] 1. The ligand parameterization process is complex and the degree of automation is low

[0064] In molecular dynamics simulations, the charge distribution and force field parameterization of small molecule ligands are key steps. However, existing tools (such as RESP charge fitting) usually require users to manually call quantum chemistry tools (such as Gaussian) for optimization and write scripts to generate force field parameters. This method is not only cumbersome and time-consuming, but also requires high professional skills of users and is prone to errors due to operation mistakes. In addition, existing platforms lack effective integration of automated ligand parameterization tools (such as ACPYPE), and users need to switch between multiple tools, and the process is not concise and efficient enough.

[0065] 2. Insufficient support for ligand position presetting and docking

[0066] In the process of constructing a protein-ligand complex system, existing technologies usually require users to manually specify the position of the ligand (such as the binding site), which is complex and error-prone for non-professional users. For cases where the ligand position is not specified, existing platforms lack an automated docking function, and users need to call molecular docking tools (such as AutoDock or Smina) by themselves to generate the binding site Pose. This process is scattered and has low connection efficiency, making it difficult to quickly complete the initialization construction of the protein-ligand complex system, especially when dealing with large-scale ligand screening, which is even more inefficient.

[0067] 3. Low sampling efficiency and insufficient enhanced sampling technology support

[0068] When conventional molecular dynamics simulations explore the free energy surface or study protein conformational changes and small molecule binding sites, they are prone to falling into local minima, resulting in low sampling efficiency and requiring long simulations to obtain sufficient results. Enhanced sampling techniques can significantly improve sampling efficiency and help users more effectively explore the dynamic behavior of complex systems. However, existing molecular dynamics platforms lack support for such techniques, and users need to manually configure complex parameters (such as temperature gradients, definition of hot regions, potential energy settings, etc.) and write control scripts. This not only increases the technical threshold but also limits the popularization of enhanced sampling techniques in practical applications, especially in application scenarios such as free energy calculations or protein-ligand binding studies.

[0069] 4. Complex operation process and unfriendly user experience

[0070] Although existing molecular dynamics simulation platforms (such as GROMACS and AMBER, etc.) are powerful, they usually rely on command-line operations or complex graphical interfaces, and users need to manually complete steps such as molecular modeling, parameter generation, and simulation settings. This results in a steep learning curve for non-professional users and makes it difficult to quickly start simulation tasks. In addition, for scenarios that require rapid screening or optimization of molecular designs, the operation processes of existing platforms are long and inefficient, making it difficult to meet the needs of efficient screening.

[0071] 5. Low cross-tool connection efficiency and poor system compatibility

[0072] When dealing with complex systems (such as protein-small molecule complexes), existing technologies usually require users to switch between multiple tools (such as quantum chemistry tools, charge fitting tools, molecular dynamics simulation tools, etc.). This cross-tool operation not only consumes time but also easily leads to simulation failures due to incompatible data formats or error propagation. In addition, existing platforms lack flexibility in supporting multiple systems (such as multi-ligand complexes or protein-small molecule complexes) and cannot effectively handle system construction and simulation in large-scale tasks.

[0073] Based on this, seeFigure 1 and Figure 2 , the present disclosure provides an automated molecular dynamics simulation method for proteins, the method comprising:

[0074] S101, obtaining a protein structure file and preprocessing the protein structure file.

[0075] S102, obtaining the type of simulation system selected by the user, and generating an independent topology file for a separate protein system corresponding to the type of simulation system or a combined topology file for a complex system of a protein and a ligand based on the preprocessed protein structure file.

[0076] S103, adding a solvation box, a water model, and ions to the generated independent topology file or combined topology file to obtain a simulation system file.

[0077] S104, obtaining the type of molecular dynamics simulation selected by the user, and generating a simulation parameter file and an automated script corresponding to the type of molecular dynamics simulation, where the type of molecular dynamics simulation includes conventional molecular dynamics simulation and molecular dynamics simulation applying enhanced sampling.

[0078] S105, executing the automated script to run the corresponding molecular dynamics simulation based on the simulation system file and the simulation parameter file to obtain an output file.

[0079] This method can be implemented through a platform as shown in Figure 12 . In a possible implementation manner, the platform can provide an interactive interface for the user to provide inputs and make relevant selections, and perform outputs after the calculation is completed.

[0080] In step S101, a protein structure file provided by the user, such as a structure file in PDB format, can be obtained first. For example, the user can upload the protein structure file on the platform for the platform to obtain. The platform can check whether the input file is complete. For example, it can check whether there are missing atoms or chains in the protein structure file. After obtaining the protein structure file, it can be preprocessed to ensure the integrity and correctness of the protein structure.

[0081] Optionally, in step S101, preprocessing the protein structure file includes:

[0082] Reading the protein structure file, and if there are unnecessary components in the protein structure file, removing the unnecessary components; if there are missing atoms or residues in the protein structure file, repairing the missing atoms or residues.

[0083] Specifically, after reading the protein structure file, its structure can be parsed, and unnecessary components such as redundant solvent molecules, ligands, and ions can be deleted. If there are missing atoms, they can be supplemented. If there are missing residues, they can be completed, structurally optimized, and force field parameters can be assigned.

[0084] Taking a single protein system as an example, the user inputs the protein structure file in PDB format with the file name 4YAY.pdb. This file contains the three-dimensional structure information of the protein, specifically including atomic coordinates, residue sequences, etc. Preprocessing is performed on it, including removing unnecessary components such as redundant ligand molecules, solvent molecules, and ions, repairing missing atoms or residues, and adding missing hydrogen atoms to ensure the integrity of the molecular structure.

[0085] Taking the protein + ligand complex system as an example, the user can input the protein structure file in PDB format with the file name 7JMT.pdb through the platform. The platform can obtain this protein structure file and perform preprocessing on it, such as repairing missing atoms or residues, removing unnecessary components, and adding missing hydrogen atoms. In addition, the user can also upload the ligand structure file, such as the file named ligand.sdf. The platform can check whether the ligand file format is correct and whether it contains the necessary chemical information.

[0086] After step S101 is completed, step S102 can be entered. In step S102, refer to Figure 3 and Figure 2 , obtain the type of simulation system selected by the user. For example, the user may select a single protein system or a protein + ligand complex system, and different types of topology files are generated corresponding to different types of systems.

[0087] Optionally, refer to Figure 3 , in step S102, obtain the type of simulation system selected by the user, and generate an independent topology file for a single protein system or a combined topology file for a protein + ligand complex system corresponding to the type of simulation system based on the preprocessed protein structure file, including:

[0088] S1021, obtain the simulation system selection information of the user to determine whether the type of simulation system selected by the user is a protein + ligand complex system.

[0089] S1022, if it is determined that the selected type of simulation system is not a protein + ligand complex system, generate an independent topology file for a single protein system based on the preprocessed protein structure file.

[0090] S1023, if it is determined that the selected type of simulation system is a protein + ligand complex system, obtain the ligand structure file provided by the user and perform preprocessing on it.

[0091] S1024. Determine whether there is a ligand parameter file provided by the user. If there is a ligand parameter file, directly obtain the ligand parameter file; if there is no ligand parameter file, automatically generate a ligand parameter file based on the preset force field.

[0092] S1025. Determine whether there is a binding position between the protein and ligand specified by the user. If there is such a binding position, based on the binding position and the ligand parameter file, combine the preprocessed protein structure file and the preprocessed ligand structure file to form a protein-ligand complex system, and generate a combined topology file for the protein-ligand complex system. If there is no such binding position, automatically use a molecular docking tool to generate the best binding site between the protein and ligand, and based on this binding site and the ligand parameter file, combine the preprocessed protein structure file and the preprocessed ligand structure file to form a protein-ligand complex system, and generate a combined topology file for the protein-ligand complex system.

[0093] In step S1021, the simulation system selection information of the user can be obtained. For example, the user can select to upload the simulation system selection information through the buttons on the platform, or reflect it through keywords in the uploaded file. See Figure 2 , this information can be information indicating whether to simulate a protein + ligand complex system. If this information indicates "yes", it can be determined that the simulation system type is a protein-ligand complex system. If this information indicates "no", it can be determined that the simulation system type is a single protein system.

[0094] After step S1021 is executed, step S1022 can be entered. If it is determined that the simulation system type selected by the user is not a protein-ligand complex system, it is determined that the user selects to simulate a single protein system. At this time, the preprocessed protein structure file can be obtained to generate an independent topology file for the single protein system, and the ligand-related processing steps can be skipped. Using the example of the aforementioned 4YAY.pdb file, the force field information selected by the user can be obtained, such as AMBER99SB or OPLS-AA, and the topology file for the single protein system can be automatically generated, including atomic types, bond lengths, bond angles, dihedral angles, and non-bonded interaction parameters.

[0095] After step S1021 is executed, step S1023 can also be entered according to the user's selection. See Figure 2 and Figure 3, if the user selects to simulate the complex system of protein and ligand, the structural file of the ligand provided by the user can be obtained, which supports SDF, MOL2 or PDB formats. Then, preprocessing is performed on the ligand structural file, including ensuring the integrity of the ligand structure and performing geometric optimization of the ligand. Continuing with the example of the aforementioned ligand.sdf file, the platform can obtain the ligand structural file ligand.sdf uploaded by the user, read its three-dimensional structure information, and perform preprocessing, specifically including performing geometric structure optimization on the ligand structural file, such as using the MMFF94 force field to perform geometric structure optimization on the ligand structural file.

[0096] After step S1023 is completed, step S1024 can be entered. In step S1024, refer to Figure 2 , it is judged whether the user provides the topological parameter file of the ligand, such as whether the ITP file in GROMACS format of the ligand is provided. If the user provides the ITP file of the ligand, the platform can directly read and use this file. If the user does not provide the ITP file, the platform can automatically generate the parameter file of the ligand (including ITP file, force field parameters and charge distribution) based on the built-in force field (such as CHARMM, AMBER or GAFF). For example, for the example of the aforementioned ligand.sdf file, if the user does not provide the ITP file, the platform can automatically generate the parameter file of the ligand based on the built-in GAFF force field, including charge distribution (based on the AM1-BCC method) and force field parameters (such as bond length, bond angle, torsion angle and non-bonded interaction parameters).

[0097] After step S1024 is completed, step S1025 can be entered. In step S1025, refer to Figure 2 , it is judged whether there is a preset binding position between the protein and the ligand. If there is a preset binding position, the platform can directly read this binding position and skip the molecular docking process. If there is no preset binding position, the platform can call a molecular docking tool (such as AutoDock or Smina) to automatically calculate the binding site Pose of the ligand and select the docking result with the highest score as the binding site. Then, the preprocessed protein structural file and the preprocessed ligand structural file can be combined using the binding position provided by the user or the generated best binding site, and the ligand parameter file provided by the user or automatically generated, to generate the combined topological file of the complex system of protein and ligand.

[0098] In this technical solution, the full-automatic processing of charge assignment and force field parameterization of small molecule ligands can be realized by integrating the ACPYPE tool. The user only needs to upload the molecular structure file, and the system can generate the topological file and parameter file of the ligand, without manually calling quantum chemistry tools or writing scripts, significantly simplifying the operation process, reducing the risk of errors, and improving efficiency and accuracy.

[0099] After step S102 is completed, step S103 can be entered. In step S103, operations such as adding a solvation box, a water model, and ions to the topology file are performed. Continuing with the example of the individual protein system mentioned above, the platform can automatically add a solvation box to the individual protein system of the independent topology file, default to the TIP3P water model, and automatically set the boundary of the water box according to the protein structure size (such as 1.0 nm). Subsequently, according to the net charge of the protein, an appropriate amount of symmetric ions (such as Na + or Cl-) are added to the simulation system to neutralize the system charge, and specific concentration of salt ions (such as 0.15 M NaCl) can be added according to user needs. Taking the above-mentioned composite system as an example, the platform can add a TIP3P water model solvation box to the composite system of the combined topology file, set the boundary (such as 1.0 nm), and add an appropriate amount of ions to neutralize the system charge.

[0100] After step S103 is completed, step S104 can be entered. In step S104, it is judged whether the user applies enhanced sampling, so as to determine whether the molecular dynamics simulation type selected by the user is conventional molecular dynamics simulation or molecular dynamics simulation applying enhanced sampling, and corresponding simulation parameter files and automation scripts are constructed. Optionally, in step S104, the molecular dynamics simulation type selected by the user is obtained, and simulation parameter files and automation scripts corresponding to the molecular dynamics simulation type are generated, including:

[0101] S1041, obtain the user's simulation type selection information to judge whether the user applies enhanced sampling.

[0102] S1042, if it is determined not to apply enhanced sampling, generate simulation parameter files and automation scripts for conventional molecular dynamics simulation.

[0103] S1043, if it is determined to apply enhanced sampling, generate simulation parameter files and automation scripts for molecular dynamics simulation applying enhanced sampling.

[0104] In step S1041, obtain the user's simulation type selection information. For example, see Figure 2 , the user selects to apply enhanced sampling or selects not to apply enhanced sampling. The user's simulation type selection information can be obtained by means of keywords in relevant files or selection buttons provided by the platform.

[0105] After step S1041 is completed, step S1042 can be entered. In step S1042, if it is determined according to the user's model type selection information that the user does not apply enhanced sampling simulation, conventional molecular dynamics simulation is adopted. For example, the platform system can automatically generate a simulation parameter file for molecular dynamics simulation, including parameter files required for each step of conventional molecular dynamics simulation, such as energy minimization, heating, pressure equilibration, and production simulation steps. In addition, an automation script for conventional molecular dynamics simulation is also generated, and the automation script includes each step of conventional molecular dynamics simulation.

[0106] Optionally, in step S1042, the automation script for conventional molecular dynamics simulation includes the following simulation calculation steps:

[0107] S10421, perform energy minimization on the individual protein system or composite system of the simulation system file to optimize the atomic positions in the simulation system file and eliminate high-energy superposition in the corresponding structure of the simulation system file.

[0108] S10422, gradually heat the corresponding system of the simulation system file to the target temperature and maintain a constant temperature.

[0109] S10423, control the pressure of the corresponding system of the simulation system file through the NPT ensemble to ensure that the equilibrium state is reached.

[0110] S10424, run production simulation under the equilibrium state to generate output files, which include a trajectory file and an energy file.

[0111] In step S10421, energy minimization is performed on the individual protein system or composite system. By adjusting the positions of the atoms in the system, the minimum energy of the system is gradually found. After step S10421 is completed, step S10422 can be entered. The simulation system is gradually heated to the target temperature, such as 300K, by heating. After step S10422 is completed, step S10423 can be entered. The pressure of the system is controlled through the constant temperature and constant pressure NPT ensemble. After the equilibrium state is reached, step S10424 is entered. A production simulation of, for example, 100 ns is performed under the equilibrium state to obtain output files such as a trajectory file and an energy file. The trajectory file can be in the xtc format, and the energy file can be in the edr format. In addition, the output file can also include a log file in the log format.

[0112] After step S1041 is completed, if the user selects to apply enhanced sampling, step S1043 can be entered. In step S1043, the configuration process of the REST2 (Replica Exchange with Solute Tempering 2) enhanced sampling technique can be optimized, enabling the user to quickly start enhanced sampling simulations without manually setting complex parameters such as temperature gradients and hot region definitions. The REST2 technique improves the conformational sampling efficiency of complex systems (such as protein-ligand complexes), reduces the risk of the system getting trapped in local energy minima, and makes the exploration of the free energy surface more efficient. The platform automatically completes the definition of the hot region and parameter configuration for enhanced sampling, significantly reducing the operation threshold.

[0113] Optionally, in step S1043, the automated script for the molecular dynamics simulation applying enhanced sampling includes the following simulation calculation steps for creating multiple replicas to run based on the REST2 enhanced sampling algorithm:

[0114] S10431, perform energy minimization on the individual protein system or complex system of the simulation system file to optimize the atomic positions in the simulation system file and eliminate the high-energy superposition in the corresponding structure of the simulation system file.

[0115] S10432, gradually heat up the corresponding system of the simulation system file to the target temperature and maintain a constant temperature.

[0116] S10433, control the pressure of the corresponding system of the simulation system file through the NPT ensemble to ensure reaching the equilibrium state.

[0117] S10434, run the production simulation in the equilibrium state to generate output files, which include a trajectory file and an energy file.

[0118] Steps S10431 to S10434 can refer to steps S10421 to S10424 of conventional molecular dynamics respectively. Different from the running mode of conventional molecular dynamics simulations, when applying the REST2 enhanced sampling technique, folders corresponding to the number of replicas will be automatically generated to execute molecular dynamics simulations according to the number of replicas and temperature range set by the user. The default number of replicas can be 16. The REST2 enhanced sampling method is an efficient enhanced sampling technique for molecular dynamics simulations. By exchanging solute molecules between replicas at different temperatures, this method can improve the sampling efficiency in the simulation, thereby more accurately studying the thermodynamic properties and kinetic processes of molecular systems. The main advantages of the REST2 method are that it does not require prior knowledge of the energy landscape information of the system to be studied and has a relatively low computational cost.

[0119] Through the above technical solutions, the obtained protein structure file can be automatically preprocessed, and based on this, an independent topology file for a separate protein system or a combined topology file for a protein-ligand complex system can be generated. A solvation box, a water model, and ions are added to the topology file to obtain a simulation system file, which is used as the input for molecular dynamics simulation. According to the user's selection, an automated script for conventional molecular dynamics simulation or molecular dynamics simulation applying enhanced sampling and a simulation parameter file required for the simulation are automatically generated. Running the automated script can execute the corresponding molecular dynamics simulation to obtain an output file containing the running results. This process does not require manual setting of complex parameters, does not require manual invocation of quantum chemistry tools or writing of scripts, realizes the full-automatic processing of molecular dynamics simulation, simplifies the operation process, reduces the risk of errors, and improves efficiency and accuracy. The provided enhanced sampling option can reduce the risk of the system falling into local energy minima and make the exploration of the free energy surface more efficient.

[0120] In addition, the present invention can support the automated processing of multiple molecular systems, including protein monomers, protein-ligand complexes, and multi-ligand complex systems. The system can automatically split the complex, generate topology files, and perform molecular modeling and simulation settings, which is particularly suitable for scenarios of multi-target drug screening or large-scale simulation. The fully automated process design improves the processing efficiency, and the user can complete the simulation without manual intervention.

[0121] Figure 4 is another flowchart of a protein automated molecular dynamics simulation method shown according to an exemplary embodiment. Refer to Figure 4 , the method includes:

[0122] S401, obtain a protein structure file and preprocess the protein structure file.

[0123] S402, obtain the type of simulation system selected by the user, and generate an independent topology file for a separate protein system or a combined topology file for a protein-ligand complex system corresponding to the type of simulation system based on the preprocessed protein structure file.

[0124] S403, add a solvation box, a water model, and ions to the generated independent topology file or combined topology file to obtain a simulation system file.

[0125] S404, obtain the type of molecular dynamics simulation selected by the user, and generate a simulation parameter file and an automated script corresponding to the type of molecular dynamics simulation. The type of molecular dynamics simulation includes conventional molecular dynamics simulation and molecular dynamics simulation applying enhanced sampling.

[0126] S405. Execute the automation script to run the corresponding molecular dynamics simulation based on the simulation system file and the simulation parameter file, and obtain an output file.

[0127] S406. Conduct result analysis based on the output file.

[0128] Among them, steps S401 to S405 can refer to steps S101 to S105 respectively. In step S406, result analysis can be performed using output files such as trajectory files and energy files. For a single protein system, result analysis can include analyzing and displaying the root mean square deviation (RMSD) of the protein simulation process, such as Figure 5 ; it can include analyzing and displaying the root mean square fluctuation (RMSF) of the protein simulation process, such as Figure 6 ; it can include analyzing and displaying the radius of gyration (Rg) of the protein simulation process, such as Figure 7 .

[0129] For a protein-ligand complex system, result analysis can include analyzing and displaying the shortest contact distance between protein residues and small molecules in the complex system, such as Figure 8 ; it can also include analyzing and displaying the MMPBSA binding energy information between protein residues and small molecules in the complex system, such as Figure 9 and Figure 10 , and it can also include analyzing and displaying the free energy landscape map of the protein in the complex system, such as Figure 11 .

[0130] Through the above technical solution, the trajectory file, energy file, and log file generated by the simulation can be automatically stored, and common analysis tools (such as free energy surface calculation, conformational clustering, and binding energy analysis) are built-in. Users can directly view or download the analysis results, which simplifies the post-processing process and further improves the overall user experience.

[0131] Figure 12 is a block diagram of a protein automated molecular dynamics simulation platform shown according to an exemplary embodiment. Refer to Figure 12 , the platform includes:

[0132] A preprocessing module for obtaining a protein structure file and preprocessing the protein structure file;

[0133] A generation module for obtaining the type of simulation system selected by the user, and generating an independent topology file for a single protein system or a joint topology file for a protein-ligand complex system corresponding to the type of simulation system based on the preprocessed protein structure file;

[0134] An addition module for adding a solvation box, a water model, and ions to the generated independent topology file or joint topology file to obtain a simulation system file;

[0135] A script module, configured to obtain the type of molecular dynamics simulation selected by a user, and generate a simulation parameter file and an automation script corresponding to the type of molecular dynamics simulation, where the type of molecular dynamics simulation includes conventional molecular dynamics simulation and molecular dynamics simulation applying enhanced sampling;

[0136] An operation module, configured to execute the automation script to run a corresponding molecular dynamics simulation based on the simulation system file and the simulation parameter file, so as to obtain an output file.

[0137] Optionally, the preprocessing module is further configured to:

[0138] Read the protein structure file, and if there are unnecessary components in the protein structure file, remove the unnecessary components, and if there are missing atoms or residues in the protein structure file, repair the missing atoms or residues.

[0139] Optionally, the generation module is further configured to obtain the type of simulation system selected by the user, and generate an independent topology file for a separate protein system or a combined topology file for a protein-ligand complex system corresponding to the type of simulation system based on the preprocessed protein structure file, including:

[0140] Obtain the simulation system selection information of the user to judge whether the type of simulation system selected by the user is a protein-ligand complex system;

[0141] If it is determined that the selected type of simulation system is not a protein-ligand complex system, generate an independent topology file for a separate protein system based on the preprocessed protein structure file;

[0142] If it is determined that the selected type of simulation system is a protein-ligand complex system, obtain the ligand structure file provided by the user and perform preprocessing;

[0143] Judge whether there is a ligand parameter file provided by the user. If there is a ligand parameter file, directly obtain the ligand parameter file; if there is no ligand parameter file, automatically generate a ligand parameter file based on a preset force field;

[0144] Determine whether there is a binding position between the user-specified protein and ligand. If such a binding position exists, based on this binding position and the ligand parameter file, combine the preprocessed protein structure file and the preprocessed ligand structure file to form a protein-ligand complex system, and generate a combined topology file for the protein-ligand complex system; if the binding position does not exist, automatically use a molecular docking tool to generate the best binding site between the protein and the ligand, and based on this binding site and the ligand parameter file, combine the preprocessed protein structure file and the preprocessed ligand structure file to form a protein-ligand complex system, and generate a combined topology file for the protein-ligand complex system.

[0145] Optionally, the script module is also used for:

[0146] Obtain the user's simulation type selection information to determine whether the user applies enhanced sampling;

[0147] If it is determined not to apply enhanced sampling, generate a simulation parameter file and an automated script for conventional molecular dynamics simulation;

[0148] If it is determined to apply enhanced sampling, generate a simulation parameter file and an automated script for molecular dynamics simulation with enhanced sampling.

[0149] Optionally, the automated script for conventional molecular dynamics simulation includes the following simulation calculation steps:

[0150] Perform energy minimization on the separate protein system or complex system of the simulation system file to optimize the atomic positions in the simulation system file and eliminate the high-energy superposition in the corresponding structure of the simulation system file;

[0151] Gradually heat up the corresponding system of the simulation system file to the target temperature and maintain a constant temperature;

[0152] Control the pressure of the corresponding system of the simulation system file through the NPT ensemble to ensure reaching an equilibrium state;

[0153] Run a production simulation in the equilibrium state to generate an output file, which includes a trajectory file and an energy file.

[0154] Optionally, the automated script for molecular dynamics simulation with enhanced sampling includes the following simulation calculation steps of running multiple replicas based on the REST2 enhanced sampling algorithm:

[0155] Perform energy minimization on the separate protein system or complex system of the simulation system file to optimize the atomic positions in the simulation system file and eliminate the high-energy superposition in the corresponding structure of the simulation system file;

[0156] Gradually heat up the corresponding system of the simulation system file to the target temperature and maintain a constant temperature;

[0157] Control the pressure of the simulation system corresponding to the simulation system file through the NPT ensemble to ensure reaching the equilibrium state;

[0158] Run the production simulation under the equilibrium state to generate an output file, which includes a trajectory file and an energy file.

[0159] Optionally, the protein automated molecular dynamics simulation platform further includes:

[0160] An output module for performing result analysis based on the output file.

[0161] Regarding the device in the above embodiments, the specific manners in which each module performs operations have been described in detail in the embodiments related to the method, and will not be elaborated here.

[0162] Figure 13 It is a block diagram of an electronic device shown according to an exemplary embodiment. As Figure 13 shown, the electronic device 700 may include: a processor 701, a memory 702. The electronic device 700 may further include one or more of a multimedia component 703, an input / output (I / O) interface 704, and a communication component 705.

[0163] Among them, the processor 701 is used to control the overall operation of the electronic device 700 to complete all or part of the steps in the above protein automated molecular dynamics simulation method. The memory 702 is used to store various types of data to support the operation of the electronic device 700. These data may include, for example, instructions for any application or method operating on the electronic device 700, as well as application-related data, such as contact data, sent and received messages, pictures, audio, video, and so on. The memory 702 can be implemented by any type of volatile or non-volatile storage device or a combination thereof, such as static random access memory (SRAM), electrically erasable programmable read-only memory (EEPROM), erasable programmable read-only memory (EPROM), programmable read-only memory (PROM), read-only memory (ROM), magnetic memory, flash memory, magnetic disk, or optical disk. The multimedia component 703 may include a screen and an audio component. Among them, the screen may be a touch screen, and the audio component is used to output and / or input audio signals. For example, the audio component may include a microphone, and the microphone is used to receive external audio signals. The received audio signals may be further stored in the memory 702 or sent through the communication component 705. The audio component also includes at least one speaker for outputting audio signals. The I / O interface 704 provides an interface between the processor 701 and other interface modules, and the above other interface modules may be a keyboard, a mouse, buttons, etc. These buttons may be virtual buttons or physical buttons. The communication component 705 is used for wired or wireless communication between the electronic device 700 and other devices. Wireless communication, such as Wi-Fi, Bluetooth, near field communication (NFC), 2G, 3G, 4G, NB-IoT, eMTC, or other 5G, etc., or a combination of one or more of them, is not limited herein. Therefore, the corresponding communication component 705 may include: a Wi-Fi module, a Bluetooth module, an NFC module, and so on.

[0164] In an exemplary embodiment, the electronic device 700 can be implemented by one or more application specific integrated circuits (ASICs), digital signal processors (DSPs), digital signal processing devices (DSPDs), programmable logic devices (PLDs), field programmable gate arrays (FPGAs), controllers, microcontrollers, microprocessors or other electronic components, and is used to execute the above-mentioned protein automated molecular dynamics simulation method.

[0165] In another exemplary embodiment, a computer-readable storage medium including program instructions is also provided. When the program instructions are executed by a processor, the steps of the above-mentioned protein automated molecular dynamics simulation method are implemented. For example, the computer-readable storage medium can be the above-mentioned memory 702 including program instructions, and the above-mentioned program instructions can be executed by the processor 701 of the electronic device 700 to complete the above-mentioned protein automated molecular dynamics simulation method.

[0166] The preferred embodiments of the present disclosure have been described in detail above with reference to the accompanying drawings. However, the present disclosure is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present disclosure, various simple modifications can be made to the technical solutions of the present disclosure, and these simple modifications all fall within the protection scope of the present disclosure.

[0167] In addition, it should be noted that, in the above specific embodiments, the various specific technical features described can be combined in any suitable manner without contradiction. To avoid unnecessary repetition, the present disclosure does not separately describe various possible combination methods.

[0168] Furthermore, any combination can be made between various different embodiments of the present disclosure as long as it does not violate the idea of the present disclosure, and it should also be regarded as the content disclosed by the present disclosure.

Claims

1. A protein automated molecular dynamics simulation method, characterized in that: The method comprises: Obtaining a protein structure file, and preprocessing the protein structure file; Obtaining the simulation system type selected by the user, and generating an independent topology file of a single protein system or a joint topology file of a complex system of a protein and a ligand corresponding to the simulation system type based on the preprocessed protein structure file; Adding a solvation box, a water model, and ions to the generated independent topology file or the combined topology file to obtain a simulation system file; Obtaining a molecular dynamics simulation type selected by a user, and generating a simulation parameter file and an automation script corresponding to the molecular dynamics simulation type, wherein the molecular dynamics simulation type includes conventional molecular dynamics simulation and molecular dynamics simulation using enhanced sampling; The automated script is executed to run a corresponding molecular dynamics simulation based on the simulation system file and the simulation parameter file to obtain an output file.

2. The method according to claim 1, characterized in that: The preprocessing of the protein structure file comprises: The protein structure file is read, and if there are non-essential components in the protein structure file, the non-essential components are removed, and if there are missing atoms or residues in the protein structure file, the missing atoms or residues are repaired.

3. The method according to claim 1, characterized in that The step of obtaining the simulation system type selected by the user and generating an independent topology file of a single protein system or a joint topology file of a complex system of a protein and a ligand corresponding to the simulation system type based on the preprocessed protein structure file includes: Acquiring the user's simulation system selection information to determine whether the simulation system type selected by the user is a composite system of protein and ligand; If it is determined that the selected simulation system type is not a complex system of protein and ligand, an independent topology file of a separate protein system is generated based on the preprocessed protein structure file; If the selected simulation system type is determined to be a composite system of protein and ligand, obtain the ligand structure file provided by the user and perform preprocessing; Determine whether there is a ligand parameter file provided by the user. If there is a ligand parameter file, directly obtain the ligand parameter file; if there is no ligand parameter file, automatically generate the ligand parameter file based on the preset force field; Determine whether there is a binding position of the protein and the ligand specified by the user. If the binding position exists, based on the binding position and the ligand parameter file, the preprocessed protein structure file and the preprocessed ligand structure file are combined to form a complex system of the protein and the ligand, and a joint topology file of the complex system of the protein and the ligand is generated; if the binding position does not exist, a molecular docking tool is automatically used to generate the best binding site of the protein and the ligand, and based on the binding site and the ligand parameter file, the preprocessed protein structure file and the preprocessed ligand structure file are combined to form a complex system of the protein and the ligand, and a joint topology file of the complex system of the protein and the ligand is generated.

4. The method according to claim 1, characterized in that The method of obtaining the molecular dynamics simulation type selected by the user and generating a simulation parameter file and an automation script corresponding to the molecular dynamics simulation type includes: Obtaining the user's simulation type selection information to determine whether the user applies enhanced sampling; If it is determined that enhanced sampling is not to be applied, a simulation parameter file and an automated script for conventional molecular dynamics simulations are generated; If it is determined to apply enhanced sampling, a simulation parameter file and an automated script for molecular dynamics simulation using enhanced sampling are generated.

5. The method according to claim 4, characterized in that The automated script for conventional molecular dynamics simulation includes the following simulation calculation steps: Minimize the energy of a single protein system or a complex system in the simulation system file to optimize the atomic positions in the simulation system file and eliminate the high energy superposition in the corresponding structure of the simulation system file; Gradually heat up the corresponding system of the simulation system file to the target temperature and keep the temperature constant; The pressure of the corresponding system in the simulation system file is controlled by the NPT ensemble to ensure that the equilibrium state is reached; A production simulation is run at equilibrium to generate output files including trajectory files and energy files.

6. The method according to claim 4, characterized in that The automated script for molecular dynamics simulation using enhanced sampling includes the following simulation calculation steps of creating multiple replicas based on the REST2 enhanced sampling algorithm: Minimize the energy of a single protein system or a complex system in the simulation system file to optimize the atomic positions in the simulation system file and eliminate the high energy superposition in the corresponding structure of the simulation system file; Gradually heat the corresponding system of the simulation system file to the target temperature and maintain a constant temperature The pressure of the corresponding system in the simulation system file is controlled by the NPT ensemble to ensure that the equilibrium state is reached; A production simulation is run at equilibrium to generate output files including trajectory files and energy files.

7. The method according to claim 1, characterized in that The method further comprises: A result analysis is performed based on the output file.

8. A protein automated molecular dynamics simulation platform, characterized in that: The platform includes: A preprocessing module, used for obtaining a protein structure file and preprocessing the protein structure file; A generation module, used to obtain the simulation system type selected by the user, and generate an independent topology file of a single protein system or a joint topology file of a complex system of protein and ligand corresponding to the simulation system type based on the preprocessed protein structure file; An adding module is used to add a solvation box, a water model and ions to the generated independent topology file or the combined topology file to obtain a simulation system file; A script module, used to obtain a molecular dynamics simulation type selected by a user, and generate a simulation parameter file and an automation script corresponding to the molecular dynamics simulation type, wherein the molecular dynamics simulation type includes conventional molecular dynamics simulation and molecular dynamics simulation using enhanced sampling; The computing module is used to execute the automated script to run the corresponding molecular dynamics simulation based on the simulation system file and the simulation parameter file to obtain an output file.

9. A computer-readable storage medium having a computer program stored thereon, characterized in that: When the program is executed by a processor, the steps of the method described in any one of claims 1 to 7 are implemented.

10. An electronic device, characterized in that: include: a memory having a computer program stored thereon; A processor, configured to execute the computer program in the memory to implement the steps of the method according to any one of claims 1 to 7.

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