阅读说明：本技术 一种药物分子动力学模拟限制势方法及系统 (Method and system for simulating restriction potential by using drug molecular dynamics ) 是由 刘锴 谢雅榆 黄炳耀 刘永宏 高程海 阳蓝田 谢沛桃 于 2021-01-18 设计创作，主要内容包括：本发明涉及药物设计技术领域,尤其是一种药物分子动力学模拟限制势方法及系统包括下述步骤：通过常规动力学模拟计算,获得分子的动力学轨迹：设定采样平衡区域,并读取所述采样平衡区域内,所述分子中所有原子随时间位置变化的轨迹；计算所述分子中各个原子位置坐标随时间变化的平均值,并将各个原子按照所述平均值由小到大排序；根据预设的创建量,根据所述创建量创建参考原子列表；在所述参考原子列表中获取参考原子,根据所述参考原子的序号并通过计算所述参考原子的键长、键夹角及二面角的简谐振动常数,以获得分子的限制势。本发明合理的选择参考原子,避免因参考原子选择不当,而产生的计算的误差甚至错误。(The invention relates to the technical field of drug design, in particular to a method and a system for simulating a restriction potential of drug molecular dynamics, which comprises the following steps: by conventional kinetic simulation calculations, kinetic trajectories of molecules were obtained: setting a sampling balance area, and reading the locus of all atoms in the molecule changing along with the position of the time in the sampling balance area; calculating the average value of the position coordinates of each atom in the molecule along with the change of time, and sequencing each atom from small to large according to the average value; creating a reference atom list according to a preset creating amount and the creating amount; and acquiring reference atoms from the reference atom list, and calculating the bond length, the bond angle and the simple harmonic vibration constant of the dihedral angle of the reference atoms according to the serial numbers of the reference atoms to obtain the molecular limit potential. The invention reasonably selects the reference atoms, and avoids the calculation error and even error caused by improper selection of the reference atoms.)

1. A method for simulating a confining potential in the pharmacokinetics, comprising the steps of:

s1, obtaining a kinetic trajectory of molecules through conventional kinetic simulation calculation:

s2, setting a sampling balance area, and reading the track of all atoms in the molecule changing along with the position in the sampling balance area;

s3, calculating an average value of position coordinates of all atoms in the molecules along with time change, and sequencing all atoms from small to large according to the average value;

s4, according to a preset creation amount, acquiring the atoms corresponding to the creation amount in the step S3 as a reference atom list;

and S5, acquiring reference atoms from the reference atom list, and calculating the bond length, the bond included angle and the simple harmonic vibration constant of the dihedral angle of the reference atoms according to the serial numbers of the reference atoms to obtain the molecular limit potential.

2. A method as in claim 1 wherein said method comprises: in step S1, the kinetic trajectory of the molecule includes a protein kinetic trajectory and a small molecule kinetic trajectory.

3. A method according to claim 2, wherein said method comprises the steps of: in step S3, the average value of the time-dependent change in the position coordinates of each atom in the protein and the small molecule position change trajectory file is calculated.

4. A method according to claim 3, wherein said method comprises the steps of: in step S4, the created amount of the protein and the atoms corresponding to the small molecules are obtained as a protein reference atom list and a small molecule reference atom list, respectively.

5. A method according to claim 4, wherein said method comprises the steps of: in step S5, the reference atom acquiring step includes:

a1, respectively obtaining the first atom sequence numbers of the protein reference atom list and the small molecule reference atom list, and marking as a protein reference atom P1 and a small molecule reference atom L1;

a2, sequentially calculating the space distances between the protein reference atom P1 and other reference atoms in the protein reference atom list, and marking the reference atom with the maximum space distance as a protein reference atom P2; sequentially calculating the spatial distances between the small molecule reference atom L1 and other reference atoms in the small molecule reference atom list, and marking the reference atom with the maximum spatial distance as a small molecule reference atom L2;

a3, sequentially and respectively calculating the sum of the spatial distances between the protein reference atom P1 and the protein reference atom P2 and other reference atoms in the protein reference atom list, and taking the reference atom corresponding to the maximum value of the spatial distances as a protein reference atom P3; and sequentially and respectively calculating the sum of the spatial distances between the small molecule reference atom L1 and the small molecule reference atom L2 and other reference atoms in the small molecule reference atom list, and taking the reference atom corresponding to the maximum value of the spatial distances as the small molecule reference atom L3.

6. A method according to claim 5, wherein said method comprises the steps of: in step S5, according to the sequence numbers of the protein reference atom and the small molecule reference atom, simple harmonic vibration constants of the bond length, the bond angle and the dihedral angle between the protein reference atom P1 and the small molecule reference atom L1, the protein reference atom P2 and the small molecule reference atom L2 and the protein reference atom P3 and the small molecule reference atom L4 are calculated to obtain the value of the molecular confinement potential.

7. A method as in claim 1 wherein said method comprises: the created amount is the first 50% of the atomic sequence.

8. A system according to any one of claims 1-7 for simulating a molecular dynamics potential-limiting system for use in a method of simulating a molecular dynamics potential-limiting of a drug, comprising: comprises a sampling execution module (1), a sampling balance area setting module (2), a sampling stability analysis module (3), a reference atom establishing module (4) and a limit potential calculation module (5),

the sampling execution module (1) is used for conventional kinetic simulation calculation of the molecule to obtain a kinetic trajectory of the molecule;

the sampling balance area setting module (2) is used for setting a sampling balance area, and the sampling balance area setting module (2) can read the locus of all atoms in the molecule changing along with the position of the time in the sampling balance area;

the sampling stability analysis module (3) is used for acquiring data of the sampling balance region setting module (2), and the sampling stability analysis module (3) calculates an average value of position coordinates of each atom in the molecule along with time variation;

the reference atom establishing module (4) is used for acquiring data of the sampling stability analysis module (3), and sequencing all atoms from small to large according to the average value, wherein the atoms according to a preset creation amount are used as a reference atom list; and the reference atom creation module (4) obtains a reference atom in the reference atom list;

and the limit potential calculation module (5) is used for calculating the simple harmonic vibration constants of the bond length, the bond included angle and the dihedral angle of the reference atoms according to the sequence numbers of the protein reference atoms and the small molecule reference atoms so as to obtain the limit potential of the molecules.

9. A system according to claim 8, wherein said system comprises: still include sampling detection module (11), adopt inspection module (11) to be used for acquireing the data of sampling balance region setting module (2) to right the kinetic trajectory of molecule carries out index parameter detection, just when index parameter is less than the threshold value, sampling detection module (11) control sampling balance region setting module (2) carries out conventional dynamics simulation calculation again to the time of the analog sampling of extension conventional dynamics.

Technical Field

The invention relates to the technical field of drug design, in particular to a method and a system for simulating a restriction potential of drug molecular dynamics.

Background

With the development of high-performance computing technology, the pharmacokinetic simulation is gradually becoming the most important theoretical computing means for predicting the binding activity of small drug molecules and target proteins. The introduction of the limiting potential can increase the sampling efficiency in unit simulation time, and is the key for improving the prediction precision of the binding activity. Borech et al, 2003, gave a calculation of the restriction potential (Borech, S.; Tettinger, F.; Leitgeb, M.; Karplus, M., Absolute Binding Free Energies: A Quantitative Approach for the theory of Calculation.J.Phys. chem.B 2003,107, 9535-. Theoretically, for a simulation system in an equilibrium state, a reference atom can be selected at will, and the magnitude of the calculation limit potential is not influenced; however, in the practical application process, because the dynamic simulation sampling time is limited, the selection of different reference atoms has a great influence on the repeatability and accuracy of the calculation.

Disclosure of Invention

In order to solve the above problems, the present invention provides a method and a system for simulating a restriction potential of a drug molecule dynamics, which reasonably selects a reference atom and avoids calculation errors and even errors caused by improper selection of the reference atom.

In order to achieve the purpose, the invention adopts the technical scheme that:

a method for simulating a restriction potential in the pharmacokinetics, comprising the steps of:

s1, obtaining a kinetic trajectory of molecules through conventional kinetic simulation calculation:

s2, setting a sampling balance area, and reading the track of all atoms in the molecule changing along with the position in the sampling balance area;

s3, calculating an average value of position coordinates of all atoms in the molecules along with time change, and sequencing all atoms from small to large according to the average value;

s4, according to a preset creation amount, acquiring the atoms corresponding to the creation amount in the step S3 as a reference atom list;

and S5, acquiring reference atoms from the reference atom list, and calculating the bond length, the bond included angle and the simple harmonic vibration constant of the dihedral angle of the reference atoms according to the sequence numbers of the reference atoms to obtain the molecular limit potential.

Further, in step S1, the kinetic trajectory of the molecule includes a protein kinetic trajectory and a small molecule kinetic trajectory.

Further, in step S3, an average value of the temporal change of the position coordinates of each atom in the protein and the small molecule position change trajectory file is calculated.

Further, in step S4, the created amount of the protein and the atoms corresponding to the small molecules are obtained as a protein reference atom list and a small molecule reference atom list, respectively.

Further, in step S5, the reference atom acquiring step includes:

a1, respectively obtaining the first atom sequence numbers of the protein reference atom list and the small molecule reference atom list, and marking as a protein reference atom P1 and a small molecule reference atom L1;

a2, sequentially calculating the space distances between the protein reference atom P1 and other reference atoms in the protein reference atom list, and marking the reference atom with the maximum space distance as a protein reference atom P2; sequentially calculating the spatial distances between the small molecule reference atom L1 and other reference atoms in the small molecule reference atom list, and marking the reference atom with the maximum spatial distance as a small molecule reference atom L2;

a3, sequentially and respectively calculating the sum of the spatial distances between the protein reference atom P1 and the protein reference atom P2 and other reference atoms in the protein reference atom list, and taking the reference atom corresponding to the maximum value of the spatial distances as a protein reference atom P3; and sequentially and respectively calculating the sum of the spatial distances between the small molecule reference atom L1 and the small molecule reference atom L2 and other reference atoms in the small molecule reference atom list, and taking the reference atom corresponding to the maximum value of the spatial distances as the small molecule reference atom L3.

Further, in step S5, according to the sequence numbers of the protein reference atom and the small molecule reference atom, the simple harmonic vibration constants of the bond length, the bond angle and the dihedral angle between the protein reference atom P1 and the small molecule reference atom L1, the protein reference atom P2 and the small molecule reference atom L2 and the protein reference atom P3 and the small molecule reference atom L4 are calculated to obtain the values of the molecular confinement potential.

Further, the created amount is the first 50% of the atomic sequence.

Further comprises a sampling execution module, a sampling balance area setting module, a sampling stability analysis module, a reference atom establishing module and a limit potential calculation module,

the sampling execution module is used for conventional kinetic simulation calculation of the molecules so as to obtain kinetic tracks of the molecules;

the sampling balance area setting module is used for setting a sampling balance area, and the sampling balance area setting module can read the locus of all atoms in the molecule changing along with the position in the sampling balance area;

the sampling stability analysis module is used for acquiring data of the sampling balance area setting module, and calculating an average value of position coordinates of each atom in the molecule along with time variation by the sampling stability analysis module;

the reference atom establishing module is used for acquiring data of the sampling stability analysis module, and sequencing all atoms from small to large according to the average value, and taking the atoms according to a preset creating amount as a reference atom list; the reference atom establishing module acquires a reference atom from the reference atom list;

and the limit potential calculation module is used for calculating the simple harmonic vibration constants of the bond length, the bond included angle and the dihedral angle of the reference atoms according to the sequence numbers of the protein reference atoms and the small molecule reference atoms so as to obtain the limit potential of the molecules.

Further, the dynamic trajectory analysis device further comprises a sampling detection module, wherein the sampling detection module is used for acquiring data of the sampling balance area setting module so as to detect index parameters of the dynamic trajectory of the molecule, and when the index parameters are lower than a threshold value, the sampling detection module controls the sampling balance area setting module to perform conventional dynamic simulation calculation again and prolong the time of conventional dynamic simulation sampling.

The invention has the beneficial effects that:

the method comprises the steps of calculating molecules by utilizing conventional dynamics simulation, obtaining a section of kinetic trajectory of the molecules, calculating the average value of position coordinates of atoms in the molecules along with time after dividing the kinetic trajectory, creating a reference atom list according to the average value, obtaining reference atoms in the reference atom list, and finally obtaining the limit potential of the molecules by calculating the bond length, the bond included angle and the simple harmonic vibration constant of the dihedral angle of the reference atoms. Meanwhile, the calculation method of the automatic limit potential enables the calculation of the reference potential to be carried out without manual intervention, simplifies complex operation and ensures the repeatability and accuracy of the calculation result. And through reasonable selection of the reference atoms, errors and even errors of calculation caused by improper selection of the reference atoms are avoided.

Drawings

FIG. 1 is a flow chart of a method for simulating a restriction potential in molecular dynamics of a drug in accordance with a preferred embodiment of the present invention.

FIG. 2 is a flow chart of the reference atom acquisition process of the method for simulating the confinement potential of the molecular dynamics of a drug in accordance with a preferred embodiment of the present invention.

FIG. 3 is a flow chart of the molecular confinement potential calculation of the method for simulating the confinement potential of the molecular dynamics of a drug in accordance with a preferred embodiment of the present invention.

FIG. 4 is a block diagram of the structure of the biomolecular dynamics simulation potential-limiting system according to a preferred embodiment of the present invention.

In the figure, the device comprises a 1-sampling execution module, a 11-sampling detection module, a 2-sampling balance region setting module, a 3-sampling stability analysis module, a 4-reference atom establishment module and a 5-limit potential calculation module.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

Referring to fig. 1 to 4, the method for simulating a restriction potential of a molecular dynamics of a drug according to a preferred embodiment of the present invention includes the following steps:

s1, obtaining a kinetic trajectory of molecules through conventional kinetic simulation calculation. The kinetic trajectory of the molecule includes a protein kinetic trajectory and a small molecule kinetic trajectory.

And S2, setting a sampling balance area, and reading the track of all atoms in the molecule changing along with the position in the sampling balance area.

And S3, calculating the average value of the position coordinates of each atom in the molecule along with the change of time, and sequencing each atom from small to large according to the average value. In this embodiment, the average value of the position coordinates of each atom in the protein and small molecule position change trajectory file over time is calculated.

And S4, acquiring atoms corresponding to the creation amount in the step S3 as a reference atom list according to the preset creation amount. The reference atom lists serve as a protein reference atom list and a small molecule reference atom list respectively.

As shown in fig. 2, the reference atom acquiring step includes:

a1, respectively obtaining the first atom sequence numbers of a protein reference atom list and a small molecule reference atom list, and marking as a protein reference atom P1 and a small molecule reference atom L1;

a2, sequentially calculating the space distances between the protein reference atom P1 and other reference atoms in the protein reference atom list, and marking the reference atom with the maximum space distance as a protein reference atom P2; sequentially calculating the spatial distances between the small molecule reference atom L1 and other reference atoms in the small molecule reference atom list, and marking the reference atom with the maximum spatial distance as a small molecule reference atom L2;

a3, sequentially and respectively calculating the sum of the spatial distances between a protein reference atom P1 and the protein reference atom P2 and other reference atoms in the protein reference atom list, and taking the reference atom corresponding to the maximum value of the spatial distances as a protein reference atom P3; and sequentially and respectively calculating the sum of the spatial distances between the small molecule reference atom L1 and the small molecule reference atom L2 and other reference atoms in the small molecule reference atom list, and taking the reference atom corresponding to the maximum value of the spatial distances as the small molecule reference atom L3.

Preferably, the amount is created to be the first 50% of the atomic sequence, such that the first 50% of the atoms of step S3 arranged by mean are taken as the protein reference atom list and the small molecule reference atom list.

And S5, acquiring reference atoms from the reference atom list, and calculating the bond length, the bond angle and the simple harmonic vibration constant of the dihedral angle of the reference atoms according to the serial numbers of the reference atoms to obtain the molecular limit potential. As shown in fig. 3, in the present embodiment, according to the sequence numbers of the protein reference atom and the small molecule reference atom, the simple harmonic vibration constants of the bond length, the bond angle and the dihedral angle between the protein reference atom P1 and the small molecule reference atom L1, the protein reference atom P2 and the small molecule reference atom L2, and the protein reference atom P3 and the small molecule reference atom L4 are calculated to obtain the value of the molecular confinement potential.

In the embodiment, the molecule is calculated by using conventional dynamics simulation, so that a section of kinetic trajectory of the molecule can be obtained, after the kinetic trajectory is divided, the average value of the position coordinates of each atom in the molecule, which changes along with time, is calculated, so that a reference atom list can be created according to the average value, reference atoms are obtained in the reference atom list, and finally, the limit potential of the molecule is obtained by calculating the bond length, the bond angle and the simple harmonic vibration constant of the dihedral angle of the reference atoms, so that the automatic reference atom selection calculation technology is realized, the operation is simple, the uniqueness of reference atom selection in the operation process is ensured, and the calculation error can be effectively avoided. Meanwhile, the calculation method of the automatic limit potential enables the calculation of the reference potential to be carried out without manual intervention, simplifies complex operation and ensures the repeatability and accuracy of the calculation result.

The drug molecular dynamics simulation limit potential system adopted by the drug molecular dynamics simulation limit potential method comprises a sampling execution module 1, a sampling balance area setting module 2, a sampling stability analysis module 3, a reference atom establishing module 4 and a limit potential calculation module 5,

the sampling execution module 1 is used for conventional kinetic simulation calculations of molecules to obtain kinetic trajectories of the molecules.

The sampling balance area setting module 2 is used for setting a sampling balance area, and the sampling balance area setting module 2 can read the locus of all atoms in a molecule changing along with the position of the molecule in the sampling balance area.

The sampling stability analysis module 3 is used for acquiring data of the sampling balance area setting module 2, and the sampling stability analysis module 3 calculates an average value of position coordinates of each atom in the molecule along with time variation.

The reference atom establishing module 4 is used for acquiring data of the sampling stability analysis module 3, and sequencing the atoms from small to large according to the average value, and taking the atoms according to the preset creating amount as a reference atom list; and the reference atom creation module 4 retrieves the reference atoms in the reference atom list.

And the limit potential calculation module 5 is used for calculating simple harmonic vibration constants of the bond length, the bond angle and the dihedral angle of the reference atom according to the reference atom so as to obtain the limit potential of the molecule.

Preferably, the dynamic kinetic simulation system further comprises a sampling detection module 11, wherein the inspection module 11 is used for acquiring data of the sampling balance area setting module 2 so as to detect index parameters of the kinetic trajectory of the molecule, and when the index parameters are lower than a threshold value, the sampling detection module 11 controls the sampling balance area setting module 2 to perform conventional dynamic simulation calculation again and prolongs the time of conventional dynamic simulation sampling. The index parameters include density, kinetic energy, potential energy, and the like.

Under the action of the sampling detection module 11, the balance region setting module 2 can ensure that the motion trail of the molecule reaches a balance state.

The molecular dynamics simulation potential limiting system of the embodiment can automatically and reasonably select the reference atoms, and avoids calculation errors and even errors caused by improper selection of the reference atoms. And the limit potential can be automatically calculated and output, so that the difference of calculation results caused by different operators is reduced, and data errors are avoided.