Enhanced sampling method and method for calculating binding free energy of complexes

Abstract

The present invention relates to the field of drug development technology, and in particular to an enhanced sampling method and a method for calculating the binding free energy of a complex. The enhanced sampling method includes: determining the temperature rise region of a target molecule-protein complex; modifying the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature rise region, obtaining the force field parameters of the target molecule-protein complex system based on the modified system, and then further generating the parameter file required for FEP / REST2 simulation; using the parameter file as the input of the potential function to perform FEP / REST2 simulation to generate a trajectory file. The present application modifies the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the determined temperature rise region, and quickly and conveniently implements the process of the REST2 method in a way that minimizes code modification, which is simple to operate and improves the calculation efficiency and prediction accuracy of subsequent FEP.

Description

Technical Field

[0001] The present application relates to the field of drug development technology, and in particular to an enhanced sampling method, a method for calculating the binding free energy of a target molecule-protein complex, an enhanced sampling device, a device for calculating the binding free energy of a target molecule-protein complex, an electronic device, and a computer-readable storage medium. Background Art

[0002] As an indicator for evaluating the activity of drug molecules, the binding free energy between drug molecules and proteins can be predicted by a variety of computational methods. Among them, free energy perturbation (FEP) is a high-precision computational chemistry prediction method that has been widely used in drug design. However, as a method based on molecular dynamics simulation, FEP often faces sampling problems during the simulation process. For systems with insufficient sampling, the obtained binding free energy cannot converge well, which greatly affects the accuracy of the prediction results.

[0003] In order to solve this problem, there are various enhanced sampling methods in the prior art. Among them, Replica Exchange with Solute Tempering (REST2) is an enhanced sampling method in computational chemistry, which was originally designed to be mainly used for the simulation of protein folding systems. The REST2 method uses the idea of ​​local (hot region) heating to reduce the number of required exchange copies while ensuring the exchange rate, thereby achieving efficient and reliable enhanced sampling. Many studies have shown that the use of the REST2 method for enhanced sampling of FEP (hereinafter referred to as FEP / REST2) can significantly improve the calculation accuracy of FEP. However, the inventors of the present application have found in long-term research that there are two problems when using FEP / REST2: 1. The use of the REST2 method in FEP involves the modification of the underlying code of the molecular dynamics software, which is difficult to implement; 2. The overall process of the FEP / REST2 method is complex and difficult to use. Summary of the invention

[0004] The main purpose of the present application is to provide an enhanced sampling method, a method for calculating the binding free energy of a target molecule-protein complex, an enhanced sampling device, a device for calculating the binding free energy of a target molecule-protein complex, an electronic device, and a computer-readable storage medium, so as to solve the problem in the prior art that the REST2 method is difficult to implement and use in FEP.

[0005] An enhanced sampling method provided in an embodiment of the present application includes:

[0006] Determine the temperature rise area of ​​the target molecule-protein complex;

[0007] Modifying the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature rise region to obtain the modified force field parameters of the target molecule-protein complex system, and then further generating the parameter file required for FEP / REST2 simulation;

[0008] The parameter file is used as an input of a potential function to perform FEP / REST2 simulation to generate a trajectory file, which is used to calculate the binding free energy of the target molecule-protein complex.

[0009] The present application provides a method for calculating the binding free energy of a target molecule-protein complex, comprising:

[0010] Construct the initial input file of the target molecule-protein complex system;

[0011] Inputting the initial input file into the enhanced sampling method as described in the above embodiment to obtain a trajectory file;

[0012] The binding free energy of the target molecule-protein complex is obtained based on the trajectory file.

[0013] An enhanced sampling device provided in an embodiment of the present application includes:

[0014] A temperature rise region determination module, used to determine the temperature rise region of the target molecule-protein complex;

[0015] A force field parameter modification module, used to modify the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature increase region, obtain the modified force field parameters of the target molecule-protein complex system, and then further generate a parameter file required for FEP / REST2 simulation; and

[0016] A trajectory file generation module is used to use the parameter file as an input of a potential function to perform FEP / REST2 simulation to generate a trajectory file, wherein the trajectory file is used to calculate the binding free energy of the target molecule-protein complex.

[0017] An embodiment of the present application provides a device for calculating the binding free energy of a target molecule-protein complex, comprising:

[0018] Construction module, used to construct the initial input file of the target molecule-protein complex system;

[0019] The enhanced sampling device as described in the above embodiment is used to obtain a trajectory file based on the input initial input file; and

[0020] A calculation module is used to obtain the binding free energy of the target molecule-protein complex based on the trajectory file.

[0021] An electronic device provided in an embodiment of the present application includes:

[0022] one or more processors;

[0023] A memory, coupled to the processor, for storing one or more programs;

[0024] When the one or more programs are executed by the one or more processors, the one or more processors implement the enhanced sampling method described in the above embodiments or the method for calculating the binding free energy of the target molecule-protein complex described in the above embodiments.

[0025] An embodiment of the present application provides a computer-readable storage medium having a computer program stored thereon. When the computer program is executed by a processor, the enhanced sampling method described in any embodiment or the method for calculating the binding free energy of a target molecule-protein complex described in the above embodiments is implemented.

[0026] Compared with the prior art, the enhanced sampling method, enhanced sampling method, method for calculating the binding free energy of a target molecule-protein complex, electronic device, and computer-readable storage medium of the present application have the following beneficial effects:

[0027] Since the energy of the target molecule-protein complex system can be calculated by the potential function in the molecular dynamics simulation, the present application determines the temperature rise region of the target molecule-protein complex and then modifies the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature rise region, that is, modifies various parameters in the potential function to generate the parameter file required for the FEP / REST2 simulation, thereby quickly and conveniently implementing the process of the REST2 method with minimal code modification, without significantly modifying the underlying code of the molecular dynamics simulation software, and is simple to operate, thereby improving the calculation efficiency and prediction accuracy of subsequent FEP. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The present application will illustrate the implementation methods in conjunction with the accompanying drawings. The accompanying drawings of the present application are only used to describe the embodiments for the purpose of demonstration. Without departing from the principles of the present application, those skilled in the art can easily make other embodiments according to the steps described below through the following description.

[0029] Figure 1 The figure is a flow chart of an enhanced sampling method in an embodiment of the present application.

[0030] Figure 2 This is a schematic diagram of a specific process for determining the heating area in step S10 in an embodiment of the present application.

[0031] Figure 3 This is a schematic diagram of a specific process of modifying the force field parameters of the target molecule-protein complex system corresponding to the temperature rising region in step S20 in an embodiment of the present application.

[0032] Figure 4 Schematic diagram of a method for calculating the binding free energy of a target molecule-protein complex in an embodiment of the present application.

[0033] Figure 5 This is a schematic diagram of the basic principle of using relative free energy to calculate the free energy difference between different molecules in the embodiments of the present application.

[0034] Figure 6(a) is a schematic diagram of the FEP calculation results when REST2 enhanced sampling is not used.

[0035] FIG6( b ) is a schematic diagram of the FEP calculation results when using the REST2 enhanced sampling of the present application.

[0036] Figure 7 This is a schematic diagram of the structure of an enhanced sampling device in an embodiment of the present application.

[0037] Figure 8 Schematic diagram of the structure of a device for calculating the binding free energy of a target molecule-protein complex in an embodiment of the present application.

[0038] Fig. 9 This is a schematic diagram of the structure of an electronic device in an embodiment of the present application. DETAILED DESCRIPTION

[0039] The technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. It will be understood that the specific embodiments described herein are only used to explain the present application, rather than to limit the present application. It should also be noted that, for ease of description, only some but not all structures related to the present application are shown in the drawings. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without making creative work are within the scope of protection of the present application.

[0040] The terms "first", "second", etc. in this application are used to distinguish different objects, rather than to describe a specific order. In addition, the terms "including" and "having" and any variations thereof are intended to cover non-exclusive inclusions. For example, a process, method, system, product or device that includes a series of steps or units is not limited to the listed steps or units, but optionally includes steps or units that are not listed, or optionally includes other steps or units inherent to these processes, methods, products or devices.

[0041] Reference to "embodiments" herein means that a particular feature, structure, or characteristic described in conjunction with the embodiments may be included in at least one embodiment of the present application. The appearance of the phrase in various locations in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described herein may be combined with other embodiments.

[0042] See also Figure 1 The embodiment of the present invention provides an enhanced sampling method, which is applied in common molecular simulation software to quickly and conveniently implement the process of the REST2 method in a way that minimizes code modification. Among them, the common molecular simulation software includes but is not limited to the Amber program, the Gromacs program, and the Namd program.

[0043] Specifically, the enhanced sampling method of the present application includes the following steps:

[0044] S10. Determine the temperature rise region of the target molecule-protein complex.

[0045] In this embodiment, the target molecule may be a drug candidate compound.

[0046] Free energy perturbation calculation (FEP) is a method to evaluate the binding strength between small drug molecules and targets. FEP enhances the reliability of sampling by constructing a series of non-physical intermediate states between the bound state and the unbound state. When calculating FEP, perturbation is performed by modifying lambda in the input file. In this embodiment, the temperature increase area of ​​the target molecule-protein complex is determined based on the perturbation area in the general FEP calculation process, so as to achieve local temperature increase of the target molecule-protein complex to be detected, while ensuring the exchange rate, the number of required exchange copies can be reduced, and efficient and reliable enhanced sampling can be achieved.

[0047] In a specific embodiment, Figure 2 As shown, the above step S10 includes the following steps:

[0048] The perturbation region during the FEP calculation process is determined as the initial temperature increase region of the target molecule-protein complex.

[0049] In this embodiment, the perturbation region in the general FEP calculation process is used as the initial temperature rise region.

[0050] After determining the initial temperature rise region, the structure of the target molecule is analyzed to determine whether the atom directly connected to the perturbation region is located on a ring in the target molecule. If it is located on the ring, it is determined that the perturbation region is directly connected to the ring. If it is not located on the ring, it is determined that the perturbation region is not connected to the ring. If it is determined to be connected to the ring, the ring is added to the temperature rise region. If it is determined that it is not connected to the ring, no processing is performed. This embodiment can help some systems converge faster by adding additional rings to the temperature rise region.

[0051] Specifically, the steps of analyzing the structure of the target molecule to adjust the temperature rise area are as follows:

[0052] Determining whether there is a ring in the target molecule;

[0053] If the target molecule has a ring, further determining whether at least some of the atoms in the initial temperature rise region are located on the ring, or whether at least some of the atoms in the initial temperature rise region are directly or indirectly connected to atoms on the ring;

[0054] If at least part of the atoms in the initial temperature increase region are located on the ring or directly connected to the atoms on the ring, then the region where the ring is located is added to the initial temperature increase region to obtain a first updated temperature increase region;

[0055] If at least part of the atoms in the initial temperature rise region are indirectly connected to the atoms on the ring, the ring and the region where the part indirectly connected to the ring is located are added to the initial temperature rise region to obtain a first updated temperature rise region;

[0056] If all atoms in the initial temperature-raising region are neither located on the ring nor directly or indirectly connected to atoms on the ring, the initial temperature-raising region is defined as the first updated temperature-raising region;

[0057] If there is no ring in the target molecule, the initial temperature rise region is defined as the first updated temperature rise region;

[0058] Determine whether there are additional designated areas that require heating;

[0059] If so, the additional designated area that needs to be heated is added to the first updated heating area to obtain the heating area;

[0060] If it does not exist, the first updated temperature rising area is defined as the temperature rising area.

[0061] In this way, the initial temperature rise region is updated according to the structure of the target molecule to obtain the first updated temperature rise region. After obtaining the first updated temperature rise region, it is further determined whether there is an additional designated region that needs to be heated. If so, it is added to the first temperature rise region to obtain the temperature rise region. If not, it is not added and the first updated temperature rise region is defined as the temperature rise region, thereby realizing automatic selection of the temperature rise region.

[0062] S20, modifying the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature increase region to obtain modified force field parameters of the target molecule-protein complex system, and then further generating a parameter file required for FEP / REST2 simulation.

[0063] FEP / REST2 refers to the use of the REST2 method to enhance sampling of FEP. Since the energy of the target molecule-protein complex system can be calculated by the potential function in the molecular dynamics simulation, when performing REST2 calculations on the heating region, this process can be achieved by modifying various parameters in the potential function without modifying the underlying code of the molecular dynamics simulation software.

[0064] After determining the temperature rise region, further determine the force field parameters that need to be modified for the target molecule-protein complex system so as to modify them accordingly. Specifically, the above step S20 includes the following steps:

[0065] Dividing the force field parameter items of the target molecule-protein complex system into parameters within the temperature rising region, parameters between the temperature rising region and the environment region, and parameters within the environment region;

[0066] The parameters within the temperature rising region, the parameters between the temperature rising region and the environmental region, and the parameters within the environmental region are at least partially modified to obtain the modified force field parameters of the target molecule-protein complex system, and then further generate the parameter file required for the FEP / REST2 simulation.

[0067] Based on the obtained temperature rise region, the present application can divide the target molecule-protein complex system into two parts, the temperature rise region and the environment region outside the temperature rise region, so that the total energy U of the target molecule-protein complex system under REST2 can be calculated. m REST2 It is divided into three parts (as shown in Equation 5 below): the energy Uc,c inside the heating area, the energy Uc,e between the heating area and the environment area, and the energy Ue,e inside the environment area. The basic formula of REST2 is:

[0068]

[0069]

[0070] in, is the total energy of the target molecule-protein complex system when using REST2, Uc,c is the energy inside the heating region, Uc,e is the energy between the heating region and the environment region, Ue,e is the energy inside the environment region, and k B is the Boltzmann constant, T 0 is the ambient temperature, generally 298K, T m It is the temperature of the heating area, and you can select the temperature yourself.

[0071] In molecular dynamics simulation, the above energy U can be calculated by potential function (as shown in equation 7 below). The basic potential function is shown below. During the calculation process, all parameters and variables are calculated by molecular dynamics simulation software. In this way, the energy Uc,c inside the heating region, the energy Uc,e between the heating region and the environment region, and the energy Ue,e inside the environment region can be calculated respectively, and then the total energy of the target molecule-protein complex system can be calculated.

[0072]

[0073]

[0074] in, are bonding parameters, including are the bond length coefficient, angle coefficient and dihedral coefficient respectively; ∈ i ,∈ j are the van der Waals potential well depth parameters of the i-th and j-th atoms, σ ij is the van der Waals parameter; q i ,q j is the electrostatic charge parameter of the i-th atom and the j-th atom; r i ,θ i ,φ i are the bond length parameter, angle parameter and dihedral parameter of the i-th atom, r ij is the distance between the i-th atom and the j-th atom; r 0 ,θ 0 , δ i 、n i are the bond length parameter, angle parameter, dihedral parameter of the i-th atom and the sample size included in the intermediate state i sampling.

[0075] like Figure 3As shown in the figure, according to the determined temperature rise region, the parameter k is divided into different types, including parameters within the temperature rise region, parameters between the temperature rise region and the environment region, and parameters within the environment region. At the same time, the force field parameters that need to be modified are determined, including bond length, bond angle, dihedral angle, van der Waals and electrostatic parameters.

[0076] According to the calculation formula of the potential function mentioned above, when performing REST2 calculation on the temperature rising area, this process can be realized by modifying various parameters in the potential function without modifying the underlying code of the simulation software.

[0077] Specifically, in the above step S22, at least partially modifying the parameters inside the heating area, the parameters between the heating area and the environment area, and the parameters inside the environment area includes the following steps:

[0078] Multiplying the parameter inside the temperature rising region by the first type parameter;

[0079] Multiplying the parameter between the temperature rising area and the environment area by the second type parameter;

[0080] No modification is made to the parameters inside the environmental region.

[0081] Optionally, the first type of parameters includes bonding coefficient, van der Waals coefficient and electrostatic coefficient, and the second type of parameters includes bonding coefficient.

[0082] In this embodiment, the parameters located inside the temperature rising region (including bonding parameters, van der Waals parameters and electrostatic parameters) are multiplied by the corresponding first type parameters, including bonding coefficient, van der Waals coefficient and electrostatic coefficient.

[0083] Specifically, Figure 3 As shown,

[0084] The parameters (bonding parameters) between the temperature rise region and the ambient region are modified by multiplying them by the corresponding second type parameters, where the second type parameters are the bonding coefficients between the temperature rise region and the ambient region.

[0085] It should be noted that the bonding parameters in this embodiment are parameters related to the chemical bonds used to connect atoms, such as bond length coefficient, bond angle coefficient, dihedral angle coefficient, etc.

[0086] Specifically, Figure 3 As shown,

[0087] The parameters inside the environmental area are not modified.

[0088] S30, performing FEP / REST2 simulation using the parameter file as an input of a potential function to generate a trajectory file, wherein the trajectory file is used to calculate the binding free energy of the target molecule-protein complex.

[0089] Finally, the modified parameter file potential function is input into the FEP / REST2 simulation. After the FEP / REST2 simulation generates the trajectory file, the trajectory file can be used to calculate the binding free energy of the target molecule-protein complex.

[0090] In summary, the enhanced sampling method of the present application has the following beneficial effects:

[0091] Since the energy of the target molecule-protein complex system can be calculated by the potential function in the molecular dynamics simulation, the present application determines the temperature rise region of the target molecule-protein complex and then modifies the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature rise region, that is, modifies various parameters in the potential function to generate the parameter file required for the FEP / REST2 simulation, thereby quickly and conveniently implementing the process of the REST2 method with minimal code modification, without significantly modifying the underlying code of the molecular dynamics simulation software, and is simple to operate, thereby improving the calculation efficiency and prediction accuracy of subsequent FEP.

[0092] See also Figure 4 , the embodiment of the present invention also provides a complete binding free energy calculation method. Specifically, a method of calculating the binding free energy of a target molecule-protein complex of the present application comprises the following steps:

[0093] S101. Initial input file for constructing the target molecule-protein complex system.

[0094] The initial input file contains a file of the three-dimensional conformation of the target molecule-protein complex, which may specifically be a file in pdb format.

[0095] S102: Input the initial input file into the enhanced sampling method described in any one of the above embodiments to obtain a trajectory file.

[0096] S103. Obtaining the binding free energy of the target molecule-protein complex based on the trajectory file.

[0097] In this embodiment, after the trajectory file is obtained, the trajectory file is parsed, and the molecular dynamics trajectories of the target molecule-protein complex system in different states obtained by parsing are used.

[0098] In one embodiment, before the step S101 of constructing the initial input file of the target molecule-protein complex system, the following steps are also included:

[0099] Small molecules with known small molecule-protein complex conformations were selected as reference compounds;

[0100] Determine the temperature rise region of the reference compound-protein complex;

[0101] Correspondingly, the step S20 modifies the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature rise region to obtain the modified force field parameters of the target molecule-protein complex system, and then further generates the parameter file required for FEP / REST2 simulation, including the following steps:

[0102] Modifying the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature increase region to obtain modified force field parameters of the target molecule-protein complex system;

[0103] Modifying the force field parameters of the reference compound-protein complex system in the initial input file corresponding to the temperature increase region to obtain modified force field parameters of the reference compound-protein complex system;

[0104] Based on the modified force field parameters of the reference compound-protein complex system and the modified force field parameters of the target molecule-protein complex system, the parameter file required for FEP / REST2 simulation is generated.

[0105] Furthermore, the step S103 of obtaining the binding free energy of the target molecule-protein complex based on the trajectory file is as follows: based on the trajectory file, the binding free energy of the target molecule-protein complex is obtained by calculating using the Bennett acceptance rate method.

[0106] Because the parameters of each alchemical state in the FEP calculation process are modified during the FEP calculation, the common integration method cannot be used for analysis. Therefore, the present embodiment uses the Bennett Acceptance Ratio (BAR) method to calculate the binding free energy of the target molecule-protein complex. The specific calculation method is shown in the following formula. Among them, the energy difference ΔU of the calculated trajectory file under other state parameter files can be calculated by the reweighting method, and the free energy difference ΔG between the two states can be finally obtained by the formula.

[0107] Specifically, the above step S103 further includes the following steps:

[0108] According to the two adjacent intermediate states i and j in the trajectory file, the first energy ΔU of the intermediate state i trajectory under the corresponding parameters of the intermediate state j is calculated respectively. ij, and the second energy ΔU of the intermediate state j trajectory under the corresponding parameters of the intermediate state i ji ;

[0109] The first energy ΔU ij and the second energy ΔU ji Substitute into equations 1 and 2 to calculate the solvent free energy difference ΔG of the reference compound transformed into the target molecule. A , and the binding free energy difference ΔG between the reference compound and the target molecule B ;

[0110]

[0111]

[0112] Based on the solvent free energy difference ΔG of the reference compound into the target molecule A , and the binding free energy difference ΔG between the reference compound and the target molecule B , the relative binding free energy ΔΔG of the reference compound converted into the target molecule is calculated according to formula 3 binding ;

[0113] ΔΔG binding =ΔG B -ΔG A Formula 3;

[0114] Relative binding free energy ΔΔG based on the conversion of reference compound to target molecule binding , and the binding free energy ΔG of the known reference compound-protein complex 1 , the binding free energy ΔG of the target molecule-protein complex is calculated according to formula 4 2 ;

[0115] ΔG 2 =ΔΔG binding +ΔG 1 Formula 4;

[0116] Where ΔG is the free energy difference, ΔU ij is the first energy, ΔU ji is the second energy, i is the system average in intermediate state i, <*> j is the system average in the intermediate state j, N i 、N i is the number of frames of the simulation trajectory under intermediate states i and j, k B is the Boltzmann constant, T is the simulation temperature, generally 298K, ΔΔG binding is the relative binding free energy, ΔG Ais the difference in solvent free energy between the reference compound and the target molecule, ΔG B The difference in binding free energy between the reference compound and the target molecule, ΔG 1 is the binding free energy of the known reference compound-protein complex, ΔG 2 is the binding free energy of the target molecule-protein complex.

[0117] In this example, relative binding free energy (RBFE) is used to calculate the free energy difference ΔΔG between different molecules. binding , thereby calculating the binding free energy of the target molecule-protein complex.

[0118] like Figure 5 As shown, Figure 5 To calculate the free energy difference ΔΔG between different molecules using relative binding free energy (RBFE) binding The schematic diagram of the basic principle of the reference compound A. The upper left figure shows the separation diagram of the reference compound A and the protein receptor, and the lower left figure shows the complex structure A formed by the reference compound A and the protein receptor, ΔG 1 The binding free energy of the reference compound A and the protein receptor to form a complex structure A. The upper right figure shows the separation diagram of the target molecule B and the protein receptor. The lower right figure shows the target molecule B and the protein receptor to form a complex structure B. ΔG 2 is the binding free energy of the target molecule B and the protein receptor to form a complex structure B, ΔG A is the solvent binding free energy of the protein receptor to convert the reference compound A into the target molecule B, ΔG B The difference in binding free energy between reference compound A and target molecule B.

[0119] Among them, ΔΔG binding =ΔG 2 -ΔG 1 =ΔG B -ΔG A .

[0120] To calculate ΔΔG binding , ΔG 2 -ΔG 1 It is relatively difficult to calculate, but the difference between two adjacent complex systems is small, so it is relatively easy to reach equilibrium. In actual calculations, it is easy to achieve, so a relatively simple ΔG can be calculated. B -ΔG ASpecifically, the binding free energy difference ΔG between the reference compound of the target molecule to be predicted and the target molecule is calculated by the above-mentioned method for calculating the binding free energy of the target molecule-protein complex. B and the solvent free energy ΔG of the conversion of the reference compound to the target molecule A Since a small molecule with a known small molecule-protein complex conformation is selected as the reference compound, the binding free energy ΔG of the reference compound-protein complex is 1 To determine, then through ΔG B -ΔG A Calculate ΔΔG binding After that, through ΔG 2 =ΔΔG binding +ΔG 1 (Equation 4) Calculate the binding free energy ΔG of the target molecule-protein complex 2 .

[0121] Exemplarily, the commonly used molecular simulation software Amber program is used as an example. A protein-small molecule complex is selected as a test system, and dihedral angles, van der Waals and electrostatic parameters are selected for modification to calculate the binding free energy of the protein-small molecule complex.

[0122] 1. Select small molecules with known small molecule-protein complex conformations as reference compounds and construct molecular pairs with relative free energies.

[0123] 2. Construct the initial input file of the complex system suitable for RBFE calculation based on the small molecule pair, specifically:

[0124] a. Prepare the complex structure between the reference compound and the protein, and use the molecular docking method to obtain the above-mentioned protein small molecule complex.

[0125] b. Use the Antechamber tool in Amber18 to capture the gaff2 force field parameters for each small molecule, and use the Am1bcc method to calculate the charge carried by each small molecule.

[0126] c. On this basis, the tleap tool in Amber18 is used to construct the initial input files of protein and small molecule systems.

[0127] Similarly, construct the initial input file of the target molecule-protein complex.

[0128] 3. For the initial input files of target molecule-protein complex and reference compound-protein complex, follow the above Figure 1-Figure 3 Method, modify the dihedral angle, van der Waals and electrostatic parameters respectively to obtain the force field input files required for the calculation of each intermediate state. Specifically:

[0129] a. Determine the temperature rise regions of the target molecule-protein complex and the reference compound-protein complex, respectively.

[0130] b. Modify the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature increase region to obtain the modified force field parameters of the target molecule-protein complex system.

[0131] Similarly, the force field parameters of the reference compound-protein complex system in the initial input file are modified corresponding to the temperature increase region to obtain the modified force field parameters of the reference compound-protein complex system;

[0132] c. Generate the parameter file required for FEP / REST2 simulation based on the modified force field parameters of the reference compound-protein complex system and the modified force field parameters of the target molecule-protein complex system.

[0133] 4. Perform molecular dynamics simulation on the input of each intermediate state and save the trajectory file during the simulation process.

[0134] 5. Calculate the specific relative free energy based on the obtained trajectory file and the aforementioned Bennett acceptance rate method (BAR) method. The specific process is as follows:

[0135] a. First, for two adjacent intermediate states i and j in the trajectory file, calculate the first energy ΔU of the intermediate state i trajectory under the corresponding parameters of the intermediate state j. ij , and the second energy ΔU is calculated in the same way ji ;

[0136] b. The first energy ΔU ij and the second energy ΔU ji Bring in the BAR method (as shown in Equation 1 and Equation 2 below) to calculate the solvent free energy difference ΔG of the reference compound transformed into the target molecule A , and the binding free energy difference ΔG between the reference compound and the target molecule B ;

[0137]

[0138]

[0139] c. Solvent free energy difference ΔG based on the conversion of the reference compound to the target molecule A , and the binding free energy difference ΔG between the reference compound and the target molecule B The relative binding free energy ΔΔG of the reference compound converted into the target molecule is calculated according to the following formula 3: binding ;

[0140] ΔΔGbinding =ΔG B -ΔG A Formula 3;

[0141] d. Relative binding free energy ΔΔG based on the conversion of the reference compound to the target molecule binding , and the binding free energy ΔG of the known reference compound-protein complex 1 The binding free energy ΔG of the target molecule-protein complex is calculated according to the following formula 4: 2 ;

[0142] ΔG 2 =ΔΔG binding +ΔG 1 Formula 4;

[0143] Where ΔG is the free energy difference, ΔU ij is the first energy, ΔU ji is the second energy, i is the system average in intermediate state i, <*> j is the system average in the intermediate state j, N i 、N i is the number of frames of the simulation trajectory under intermediate states i and j, k B is the Boltzmann constant, T is the simulation temperature, ΔΔG binding is the relative binding free energy, ΔG A is the difference in solvent free energy between the reference compound and the target molecule, ΔG B The difference in binding free energy between the reference compound and the target molecule, ΔG 1 is the binding free energy of the known reference compound-protein complex, ΔG 2 is the binding free energy of the target molecule-protein complex.

[0144] Thus, through ΔG B -ΔG A Calculate ΔΔG binding After that, through ΔG 2 =ΔΔG binding +ΔG 1 (Equation 4) The binding free energy ΔG of the target molecule-protein complex is finally calculated 2 .

[0145] The results calculated by the above method are compared with the experimental values, and the results are shown in Figure 6(b), where Figure 6(a) is the FEP calculation result when REST2 enhanced sampling is not used, and Figure 6(b) is the calculation result after REST2 enhanced sampling is used in this application.

[0146] Comparing the results of using FEP / REST2 in Figure 6(b) with those of not using REST2 in Figure 6(a), the mean unsigned error (MUE) is reduced after using FEP / REST2, and the correlation coefficient R 2 It can be seen that the free energy calculated by the present application is closer to the experimental result, and therefore, the enhanced sampling method and the enhanced sampling method of the present application improve the accuracy of FEP prediction.

[0147] It should be noted that in addition to using the Bennett acceptance rate method (BAR) method to calculate the binding free energy of the target molecule-protein complex, the present application may also use other methods to calculate the binding free energy of the target molecule-protein complex, which are not specifically limited here.

[0148] In summary, the method of calculating the binding free energy of the target molecule-protein complex of the present application has the following beneficial effects:

[0149] By executing the enhanced sampling method in the embodiment of the present application, the process of the REST2 method can be quickly and conveniently implemented in a manner that minimizes code modifications without significantly modifying the underlying code of the molecular dynamics simulation software, and the overall process of the FEP / REST2 method is automated, thereby improving the calculation efficiency and prediction accuracy of FEP, thereby facilitating a faster calculation of the binding free energy between the target molecule and the protein.

[0150] See also Figure 7 The embodiment of the present application further provides an enhanced sampling device 100. The enhanced sampling device 100 includes:

[0151] A temperature rise region determination module 110 is used to determine the temperature rise region of the target molecule-protein complex;

[0152] A force field parameter modification module 120, for modifying the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature increase region, obtaining the modified force field parameters of the target molecule-protein complex system, and then further generating a parameter file required for FEP / REST2 simulation; and

[0153] The trajectory file generating module 130 is used to perform FEP / REST2 simulation using the parameter file as an input of a potential function to generate a trajectory file, wherein the trajectory file is used to calculate the binding free energy of the target molecule-protein complex.

[0154] In one embodiment, the force field parameter modification module 120 includes:

[0155] A parameter division module, used for dividing the force field parameter items of the target molecule-protein complex system into parameters within the temperature rising region, parameters between the temperature rising region and the environment region, and parameters within the environment region;

[0156] The first modification module is used to at least partially modify the parameters inside the temperature rising region, the parameters between the temperature rising region and the environmental region, and the parameters inside the environmental region to obtain the modified force field parameters of the target molecule-protein complex system, and then further generate the parameter file required for the FEP / REST2 simulation.

[0157] In a certain embodiment, the first modification module is specifically used to:

[0158] Multiplying the parameter inside the temperature rising region by the first type parameter;

[0159] Multiplying the parameter between the temperature rising area and the environment area by the second type parameter;

[0160] No modification is made to the parameters inside the environmental region.

[0161] In one embodiment, the first type of parameters includes bonding coefficient, van der Waals coefficient and electrostatic coefficient, and the second type of parameters includes bonding coefficient.

[0162] In one embodiment, the temperature rise region determination module 110 is specifically used to:

[0163] The perturbation region during the FEP calculation process is determined as the initial temperature increase region of the target molecule-protein complex;

[0164] Determining whether there is a ring in the target molecule;

[0165] If the target molecule has a ring, further determining whether at least some of the atoms in the initial temperature rise region are located on the ring, or whether at least some of the atoms in the initial temperature rise region are directly or indirectly connected to atoms on the ring;

[0166] If at least part of the atoms in the initial temperature increase region are located on the ring or directly connected to the atoms on the ring, then the region where the ring is located is added to the initial temperature increase region to obtain a first updated temperature increase region;

[0167] If at least part of the atoms in the initial temperature rise region are indirectly connected to the atoms on the ring, the ring and the region where the part indirectly connected to the ring is located are added to the initial temperature rise region to obtain a first updated temperature rise region;

[0168] If all atoms in the initial temperature-raising region are neither located on the ring nor directly or indirectly connected to atoms on the ring, the initial temperature-raising region is defined as the first updated temperature-raising region;

[0169] If there is no ring in the target molecule, the initial temperature rise region is defined as the first updated temperature rise region;

[0170] Determine whether there are additional designated areas that require heating;

[0171] If so, the additional designated area that needs to be heated is added to the first updated heating area to obtain the heating area;

[0172] If it does not exist, the first updated temperature rising area is defined as the temperature rising area.

[0173] For the specific definition of the enhanced sampling device 100, please refer to the definition of the enhanced sampling method above, which will not be repeated here. Each module in the enhanced sampling device 100 can be implemented in whole or in part by software, hardware, or a combination thereof. Each of the above modules can be embedded in or independent of a processor in a computer device in the form of hardware, or can be stored in a memory in a computer device in the form of software, so that the processor can call and execute the operations corresponding to each of the above modules.

[0174] See also Figure 8 The present application also provides a device 200 for calculating the binding free energy of a target molecule-protein complex. The device 200 includes:

[0175] Construction module 210, used to construct the initial input file of the target molecule-protein complex system;

[0176] The enhanced sampling device 100 as described in any of the above embodiments is used to obtain a trajectory file based on the input initial input file; and

[0177] The calculation module 220 is used to obtain the binding free energy of the target molecule-protein complex based on the trajectory file.

[0178] In a certain embodiment, the device 200 for calculating the binding free energy of a target molecule-protein complex further includes:

[0179] A reference compound selection module, used to select small molecules with known small molecule-protein complex conformations as reference compounds;

[0180] The temperature rise region determination module 110 is also used to determine the temperature rise region of the reference compound-protein complex;

[0181] The force field parameter modification module 120 is specifically used for:

[0182] Modifying the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature increase region to obtain modified force field parameters of the target molecule-protein complex system;

[0183] Modifying the force field parameters of the reference compound-protein complex system in the initial input file corresponding to the temperature increase region to obtain modified force field parameters of the reference compound-protein complex system;

[0184] Based on the modified force field parameters of the reference compound-protein complex system and the modified force field parameters of the target molecule-protein complex system, the parameter file required for FEP / REST2 simulation is generated.

[0185] In one embodiment, the calculation module 220 includes a first sub-calculation module, and the first sub-calculation module is used to:

[0186] Based on the trajectory file, the binding free energy of the target molecule-protein complex is obtained by using the Bennett acceptance rate method for calculation;

[0187] The first sub-computing module is specifically used for:

[0188] According to the two adjacent intermediate states i and j in the trajectory file, the first energy ΔU of the intermediate state i trajectory under the corresponding parameters of the intermediate state j is calculated respectively. ij , and the second energy ΔU of the intermediate state j trajectory under the corresponding parameters of the intermediate state i ji ;

[0189] The first energy ΔU ij and the second energy ΔU ji Substitute into equations 1 and 2 to calculate the solvent free energy difference ΔG of the reference compound transformed into the target molecule. A , and the binding free energy difference ΔG between the reference compound and the target molecule B ;

[0190]

[0191]

[0192] Based on the solvent free energy difference ΔG of the reference compound into the target molecule A , and the binding free energy difference ΔG between the reference compound and the target molecule B , the relative binding free energy ΔΔG of the reference compound converted into the target molecule is calculated according to formula 3 binding ;

[0193] ΔΔG binding =ΔG B-ΔG A Formula 3;

[0194] Relative binding free energy ΔΔG based on the conversion of reference compound to target molecule binding , and the binding free energy ΔG of the known reference compound-protein complex 1 , the binding free energy ΔG of the target molecule-protein complex is calculated according to formula 4 2 ;

[0195] ΔG 2 =ΔΔG binding +ΔG 1 Formula 4;

[0196] Where ΔG is the free energy difference, ΔU ij is the first energy, ΔU ji is the second energy, i is the system average in intermediate state i, <*> j is the system average in the intermediate state j, N i 、N i is the number of frames of the simulation trajectory under intermediate states i and j, k B is the Boltzmann constant, T is the simulation temperature, ΔΔG binding is the relative binding free energy, ΔG A is the difference in solvent free energy between the reference compound and the target molecule, ΔG B The difference in binding free energy between the reference compound and the target molecule, ΔG 1 is the binding free energy of the known reference compound-protein complex, ΔG 2 is the binding free energy of the target molecule-protein complex.

[0197] The specific definition of the device 200 for calculating the binding free energy of the target molecule-protein complex can be found in the definition of the method for calculating the binding free energy of the target molecule-protein complex above, which will not be repeated here. Each module in the above-mentioned device 200 for calculating the binding free energy of the target molecule-protein complex can be implemented in whole or in part by software, hardware and a combination thereof. The above-mentioned modules can be embedded in or independent of the processor in the computer device in the form of hardware, or can be stored in the memory in the computer device in the form of software, so that the processor can call and execute the operations corresponding to the above modules.

[0198] See also Fig. 9 , an embodiment of the present application further provides an electronic device, including:

[0199] one or more processors;

[0200] A memory, coupled to the processor, for storing one or more programs;

[0201] When the one or more programs are executed by the one or more processors, the one or more processors implement the enhanced sampling method described in any of the above embodiments or the method for calculating the binding free energy of the target molecule-protein complex described in any of the above embodiments.

[0202] The processor is used to control the overall operation of the terminal device to complete all or part of the steps of the enhanced sampling method or the method for calculating the binding free energy of the target molecule-protein complex described in any of the above embodiments. The memory is used to store various types of data to support the operation of the terminal device, and these data may include, for example, instructions for any application or method used to operate on the terminal device, as well as application-related data. The memory can be implemented by any type of volatile or non-volatile storage device or a combination thereof, such as static random access memory (Static Random Access Memory, referred to as SRAM), electrically erasable programmable read-only memory (Electrically Erasable Programmable Read-Only Memory, referred to as EEPROM), erasable programmable read-only memory (Erasable Programmable Read-Only Memory, referred to as EPROM), programmable read-only memory (Programmable Read-Only Memory, referred to as PROM), read-only memory (Read-Only Memory, referred to as ROM), magnetic memory, flash memory, magnetic disk or optical disk.

[0203] In an exemplary embodiment, the terminal device can be implemented by one or more application specific integrated circuits (ASIC), digital signal processors (DSP), digital signal processing devices (DSPD), programmable logic devices (PLD), field programmable gate arrays (FPGA), controllers, microcontrollers, microprocessors or other electronic components to execute the enhanced sampling method described in any of the above embodiments or the method for calculating the binding free energy of the target molecule-protein complex described in any of the above embodiments, and achieve the technical effect consistent with the above methods.

[0204] In another exemplary embodiment, a computer-readable storage medium including a computer program is also provided, and when the computer program is executed by a processor, the steps of the enhanced sampling method described in any of the above embodiments or the method for calculating the binding free energy of the target molecule-protein complex described in any of the above embodiments are implemented. For example, the computer-readable storage medium can be the above-mentioned memory including the computer program, and the above-mentioned computer program can be executed by the processor of the terminal device to complete the enhanced sampling method described in any of the above embodiments or the method for calculating the binding free energy of the target molecule-protein complex described in any of the above embodiments, and achieve the technical effect consistent with the above methods.

[0205] The above are only preferred implementations of the present application, and are not intended to limit the patent scope of the present application. Any equivalent structure or equivalent process transformation made using the contents of the present application specification and drawings, or directly or indirectly used in other related technical fields, are also included in the patent protection scope of the present application.

Claims

1. An enhanced sampling method, It is characterized in that include: Determine the temperature rise area of ​​the target molecule-protein complex; Modifying the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature rise region to obtain the modified force field parameters of the target molecule-protein complex system, and then further generating the parameter file required for FEP / REST2 simulation; The parameter file is used as an input of a potential function to perform FEP / REST2 simulation to generate a trajectory file, which is used to calculate the binding free energy of the target molecule-protein complex.

2. The method according to claim 1, It is characterized in that The force field parameters of the target molecule-protein complex system in the initial input file are modified corresponding to the temperature rise region to obtain the modified force field parameters of the target molecule-protein complex system, and then further generate the parameter file required for FEP / REST2 simulation, including: Dividing the force field parameter items of the target molecule-protein complex system into parameters within the temperature rising region, parameters between the temperature rising region and the environment region, and parameters within the environment region; The parameters within the temperature rising region, the parameters between the temperature rising region and the environmental region, and the parameters within the environmental region are at least partially modified to obtain the modified force field parameters of the target molecule-protein complex system, and then further generate the parameter file required for the FEP / REST2 simulation.

3. The method according to claim 2, It is characterized in that The at least partially modifying the parameters inside the temperature rising area, the parameters between the temperature rising area and the environment area, and the parameters inside the environment area, comprises: Multiplying the parameter inside the temperature rising region by the first type parameter; Multiplying the parameter between the temperature rising area and the environment area by the second type parameter; No modification is made to the parameters inside the environmental region.

4. The method according to claim 3, It is characterized in that The first type of parameters includes bonding coefficient, van der Waals coefficient and electrostatic coefficient, and the second type of parameters includes bonding coefficient.

5. The method according to claim 1, It is characterized in that The step of determining the temperature rise region of the target molecule-protein complex comprises: The perturbation region during the FEP calculation process is determined as the initial temperature increase region of the target molecule-protein complex; Determining whether there is a ring in the target molecule; If the target molecule has a ring, further determining whether at least some of the atoms in the initial temperature rise region are located on the ring, or whether at least some of the atoms in the initial temperature rise region are directly or indirectly connected to atoms on the ring; If at least part of the atoms in the initial temperature increase region are located on the ring or directly connected to the atoms on the ring, then the region where the ring is located is added to the initial temperature increase region to obtain a first updated temperature increase region; If at least part of the atoms in the initial temperature rise region are indirectly connected to the atoms on the ring, the ring and the region where the part indirectly connected to the ring is located are added to the initial temperature rise region to obtain a first updated temperature rise region; If all atoms in the initial temperature-raising region are neither located on the ring nor directly or indirectly connected to atoms on the ring, the initial temperature-raising region is defined as the first updated temperature-raising region; If there is no ring in the target molecule, the initial temperature rise region is defined as the first updated temperature rise region; Determine whether there are additional designated areas that require heating; If so, the additional designated area that needs to be heated is added to the first updated heated area to obtain the heated area; If it does not exist, the first updated temperature rising area is defined as the temperature rising area.

6. A method for calculating the binding free energy of a target molecule-protein complex, It is characterized in that include: Construct the initial input file of the target molecule-protein complex system; Inputting the initial input file into the enhanced sampling method according to any one of claims 1 to 5 to obtain a trajectory file; The binding free energy of the target molecule-protein complex is obtained based on the trajectory file.

7. The method according to claim 6, It is characterized in that Before constructing the initial input file of the target molecule-protein complex system, it also includes: Small molecules with known small molecule-protein complex conformations were selected as reference compounds; Determine the temperature rise region of the reference compound-protein complex; The force field parameters of the target molecule-protein complex system in the initial input file are modified corresponding to the temperature rise region to obtain the modified force field parameters of the target molecule-protein complex system, and then further generate the parameter file required for FEP / REST2 simulation, including: Modifying the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature increase region to obtain modified force field parameters of the target molecule-protein complex system; Modifying the force field parameters of the reference compound-protein complex system in the initial input file corresponding to the temperature increase region to obtain modified force field parameters of the reference compound-protein complex system; Based on the modified force field parameters of the reference compound-protein complex system and the modified force field parameters of the target molecule-protein complex system, the parameter file required for FEP / REST2 simulation is generated.

8. The method according to claim 7, It is characterized in that The step of obtaining the binding free energy of the target molecule-protein complex based on the trajectory file is as follows: based on the trajectory file, the binding free energy of the target molecule-protein complex is obtained by using the Bennett acceptance rate method for calculation; based on the trajectory file, the binding free energy of the target molecule-protein complex is obtained by using the Bennett acceptance rate method for calculation, including: According to the two adjacent intermediate states i and j in the trajectory file, the first energy ΔU of the intermediate state i trajectory under the corresponding parameters of the intermediate state j is calculated respectively. ij , and the second energy ΔU of the intermediate state j trajectory under the corresponding parameters of the intermediate state i ji ; The first energy ΔU ij and the second energy ΔU ji Substitute into equations 1 and 2 to calculate the solvent free energy difference ΔG of the reference compound transformed into the target molecule. A , and the binding free energy difference ΔG between the reference compound and the target molecule B ; Based on the solvent free energy difference ΔG of the reference compound into the target molecule A , and the binding free energy difference ΔG between the reference compound and the target molecule B , the relative binding free energy ΔΔG of the reference compound converted into the target molecule is calculated according to formula 3 binding ; DDG binding =ΔG B -ΔG A formula 3; Relative binding free energy ΔΔG based on the conversion of the reference compound to the target molecule binding , and the binding free energy ΔG of the known reference compound-protein complex 1 , the binding free energy ΔG of the target molecule-protein complex is calculated according to formula 4 2 ; ΔG 2 =ΔΔG binding +ΔG 1 formula 4; Where ΔG is the free energy difference, ΔU ij is the first energy, ΔU ji is the second energy, i is the system average in intermediate state i, <*> j is the system average in the intermediate state j, N i 、N i is the number of frames of the simulation trajectory under intermediate states i and j, k B is the Boltzmann constant, T is the simulation temperature, ΔΔG binding is the relative binding free energy, ΔG A is the difference in solvent free energy between the reference compound and the target molecule, ΔG B The difference in binding free energy between the reference compound and the target molecule, ΔG 1 is the binding free energy of the known reference compound-protein complex, ΔG 2 is the binding free energy of the target molecule-protein complex.

9. An enhanced sampling device, It is characterized in that include: A temperature rise region determination module, used to determine the temperature rise region of the target molecule-protein complex; A force field parameter modification module is used to modify the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature increase region, obtain the modified force field parameters of the target molecule-protein complex system, and then further generate the parameter file required for FEP / REST2 simulation; and A trajectory file generation module is used to use the parameter file as an input of a potential function to perform FEP / REST2 simulation to generate a trajectory file, wherein the trajectory file is used to calculate the binding free energy of the target molecule-protein complex.

10. The device according to claim 9, It is characterized in that The force field parameter modification module comprises: A parameter division module, used for dividing the force field parameter items of the target molecule-protein complex system into parameters within the temperature rising region, parameters between the temperature rising region and the environment region, and parameters within the environment region; The first modification module is used to at least partially modify the parameters inside the temperature rising region, the parameters between the temperature rising region and the environmental region, and the parameters inside the environmental region to obtain the modified force field parameters of the target molecule-protein complex system, and then further generate the parameter file required for the FEP / REST2 simulation.

11. The device according to claim 10, It is characterized in that The first modification module is specifically used for: Multiplying the parameter inside the temperature rising region by the first type parameter; Multiplying the parameter between the temperature rising area and the environment area by the second type parameter; No modification is made to the parameters inside the environmental region.

12. The device according to claim 11, It is characterized in that The first type of parameters includes bonding coefficient, van der Waals coefficient and electrostatic coefficient, and the second type of parameters includes bonding coefficient.

13. The device according to claim 9, It is characterized in that The temperature rise area determination module is specifically used for: The perturbation region during the FEP calculation process is determined as the initial temperature increase region of the target molecule-protein complex; Determining whether there is a ring in the target molecule; If the target molecule has a ring, further determining whether at least some of the atoms in the initial temperature rise region are located on the ring, or whether at least some of the atoms in the initial temperature rise region are directly or indirectly connected to atoms on the ring; If at least part of the atoms in the initial temperature increase region are located on the ring or directly connected to the atoms on the ring, then the region where the ring is located is added to the initial temperature increase region to obtain a first updated temperature increase region; If at least part of the atoms in the initial temperature rise region are indirectly connected to the atoms on the ring, the ring and the region where the part indirectly connected to the ring is located are added to the initial temperature rise region to obtain a first updated temperature rise region; If all atoms in the initial temperature-raising region are neither located on the ring nor directly or indirectly connected to atoms on the ring, the initial temperature-raising region is defined as the first updated temperature-raising region; If there is no ring in the target molecule, the initial temperature rise region is defined as the first updated temperature rise region; Determine whether there are additional designated areas that require heating; If so, the additional designated area that needs to be heated is added to the first updated heated area to obtain the heated area; If it does not exist, the first updated temperature rising area is defined as the temperature rising area.

14. A device for calculating the binding free energy of a target molecule-protein complex, It is characterized in that include: Construction module, used to construct the initial input file of the target molecule-protein complex system; The enhanced sampling device according to any one of claims 9 to 13, used to obtain a trajectory file based on the input initial input file; and A calculation module is used to obtain the binding free energy of the target molecule-protein complex based on the trajectory file.

15. The device according to claim 14, It is characterized in that Also includes: A reference compound selection module, used to select small molecules with known small molecule-protein complex conformations as reference compounds; The temperature rise region determination module is also used to determine the temperature rise region of the reference compound-protein complex; The force field parameter modification module is specifically used for: Modifying the force field parameters of the target molecule-protein complex system in the initial input file corresponding to the temperature increase region to obtain modified force field parameters of the target molecule-protein complex system; Modifying the force field parameters of the reference compound-protein complex system in the initial input file corresponding to the temperature increase region to obtain modified force field parameters of the reference compound-protein complex system; Based on the modified force field parameters of the reference compound-protein complex system and the modified force field parameters of the target molecule-protein complex system, the parameter file required for FEP / REST2 simulation is generated.

16. The device according to claim 15, It is characterized in that The calculation module includes a first sub-calculation module, and the first sub-calculation module is used for: Based on the trajectory file, the binding free energy of the target molecule-protein complex is obtained by using the Bennett acceptance rate method for calculation; The first sub-computing module is specifically used for: According to the two adjacent intermediate states i and j in the trajectory file, the first energy ΔU of the intermediate state i trajectory under the corresponding parameters of the intermediate state j is calculated respectively. ij , and the second energy ΔU of the intermediate state j trajectory under the corresponding parameters of the intermediate state i ji ; The first energy ΔU ij and the second energy ΔU ji Substitute into equations 1 and 2 to calculate the solvent free energy difference ΔG of the reference compound transformed into the target molecule. A , and the binding free energy difference ΔG between the reference compound and the target molecule B ; Based on the solvent free energy difference ΔG of the reference compound into the target molecule A , and the binding free energy difference ΔG between the reference compound and the target molecule B , the relative binding free energy ΔΔG of the reference compound converted into the target molecule is calculated according to formula 3 binding ; DDG binding =ΔG B -ΔG A formula 3; Relative binding free energy ΔΔG based on the conversion of the reference compound to the target molecule binding , and the binding free energy ΔG of the known reference compound-protein complex 1 , the binding free energy ΔG of the target molecule-protein complex is calculated according to formula 4 2 ; ΔG 2 =ΔΔG binding +ΔG 1 formula 4; Where ΔG is the free energy difference, ΔU ij is the first energy, ΔU ji is the second energy, i is the system average in intermediate state i, <*> j is the system average in the intermediate state j, N i 、N i is the number of frames of the simulation trajectory under intermediate states i and j, k B is the Boltzmann constant, T is the simulation temperature, ΔΔG binding is the relative binding free energy, ΔG A is the difference in solvent free energy between the reference compound and the target molecule, ΔG B The difference in binding free energy between the reference compound and the target molecule, ΔG 1 is the binding free energy of the known reference compound-protein complex, ΔG 2 is the binding free energy of the target molecule-protein complex.

17. An electronic device, It is characterized in that include: one or more processors; A memory, coupled to the processor, for storing one or more programs; When the one or more programs are executed by the one or more processors, the one or more processors implement the enhanced sampling method according to any one of claims 1 to 5 or the method for calculating the binding free energy of a target molecule-protein complex according to any one of claims 6 to 8.

18. A computer-readable storage medium having a computer program stored thereon, It is characterized in that When the computer program is executed by a processor, the enhanced sampling method according to any one of claims 1 to 5 or the method for calculating the binding free energy of a target molecule-protein complex according to any one of claims 6 to 8 is implemented.

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