CN111863140B - Method for testing and fitting force field dihedral angle parameters - Google Patents
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Abstract
The invention provides a method for testing and fitting the dihedral angle parameters of a force field, which generates some representative conformations, compares the force field with a quantum chemical method for the structure, if the structure meets the standard, the force field parameters are determined to be satisfactory in performance, and the process is ended; if the standard is not met, cutting the macromolecules into molecular fragments only containing one flexible dihedral angle, scanning the dihedral angle, comparing the quantum chemical result and the force field result of each flexible dihedral angle, finding out the flexible dihedral angle which does not meet the standard, and fitting the parameters of the flexible dihedral angle; after obtaining new dihedral angle parameters, returning to a series of structures of the whole molecule generated initially for verification, if the dihedral angle parameters meet the standard, ending the whole process, and finishing the dihedral angle parameters with poor detection and fitting performance; if not, a soft dihedral that performs poorly is scanned across the molecule. The invention can complete the detection and fitting of the dihedral angle parameters of the force field by using macromolecules with lower computing resource consumption.
Description
Technical Field
The invention belongs to the field of molecular mechanics, and particularly relates to a method for testing and fitting dihedral angle parameters of a force field, which is suitable for evaluating the dihedral angle parameters in the molecular force field and fitting and correcting the parameters with poor performance.
Background
Molecular mechanics is widely used in many fields such as drug design due to its speed advantage and reliable accuracy. Molecular mechanics is based on a formula describing molecular properties (such as energy) and corresponding parameters, which are partly referred to as molecular force fields. The usual definition of force field energy is: e = Ebond+Eangle+Edihedral+Ｅimproper+Eele+EvdwIn which EbondIs the energy determined by the bond length of the two atoms to which it is attached, EangleIs the energy of the angle determined by the three atoms connected, EdidedralIs the energy of the dihedral angle determined by the four atoms connected, EimproperMaintaining the out-of-plane bending energy of four atoms of a plane in the same plane, EeleIs the energy between the charges of two atoms, EvdwIs the van der waals energy of two atoms. The corresponding bond, angle, dihedral angle, out-of-plane curvature, charge and van der waals parameters needed to calculate each energy form the force field. The dihedral angle parameter exceeds other parameters quantitatively and flexibly, so the quality of the dihedral angle parameter is critical to the overall quality of the force field.
The development of a molecular force field is generally based on smaller molecular fragments, followed by quantum chemical calculations and fitting with the calculated results (generally in terms of energy) as targets, to obtain a series of force field parameters. After this, the evaluation of the force field parametric representation usually takes as a criterion the calculated data of the quantum chemistry of some other small molecules which are not within the fitting range. Small molecules can perform a large number of accurate quantum chemical calculations. The selected quantum chemical method is generally a density functional or a high-precision method based on perturbation theory. These small molecules typically have 1-2 flexible dihedral angles. Typically, dihedral scans are rotated by these dihedral angles and are scanned at regular angular intervals in the range-180 degrees to 180 degrees. During the scanning process, the specific dihedral angle is fixed at a specific angle (typically 15 degrees) for structural optimization. And finally, comparing the energy obtained by the force field and quantum chemistry, and evaluating the force field.
As mentioned above, the development of force fields is generally based on small molecules, but in practical applications such as drug molecule design, the molecules tend to be large (more than 3 flexible angles), which requires good mobility of the force field parameters, especially the dihedral angle parameters, from small molecules to large molecules. The conventional method for detecting dihedral angle parameters and fitting new dihedral angle parameters is the above method for scanning the dihedral angles of the whole molecule (see the flow chart in fig. 1), and since large molecules contain more flexible dihedral angles and there may be coupling between the dihedral angles, the coupled dihedral angles need to be scanned in combination, so for large molecules, the conventional method needs to perform a large amount of high-precision quantum chemical calculations.
Disclosure of Invention
In view of the above technical problems, the present invention provides a method for detecting and fitting dihedral angle parameters of a macromolecular force field, which requires less calculation amount than the conventional method.
The specific technical scheme is as follows:
method for testing and fitting force field dihedral angle parameters
Firstly, generating some representative partial conformations, wherein the structures represent different angles of flexible dihedral angles in the molecule; comparing the force field with the quantum chemical method for the structures, if the force field meets the standard, determining that the force field parameters are satisfactory in performance, and ending the process;
if the two-dimensional data do not meet the standard, further cutting the macromolecules into molecular fragments only containing one flexible dihedral angle, scanning the dihedral angle, comparing the quantum chemical result of each flexible dihedral angle with the force field result, finding out the flexible dihedral angle which does not meet the standard, and fitting the parameters of the flexible dihedral angle; after obtaining new dihedral angle parameters, returning the new dihedral angle parameters to a series of initially generated structures of the whole molecule for verification, if the new dihedral angle parameters meet the standard, finishing the whole process, and finishing detecting and fitting the dihedral angle parameters with poor performance; if not, a soft dihedral with poor performance is scanned across the molecule.
The method comprises the following specific steps:
(1) for a macromolecule, rdkit was first used to generate 500 conformations per molecule (specific order is rdkit. embed multiplex cofs (mol, 500)), and these molecules were structurally optimized with the rdkit's own UFF force field (rdkit. uffgetmoleculeforcefield (mol). According to the angle distribution of the flexible dihedral angles, 30 structures are selected to cover different regions from-180 degrees to 180 degrees, and because the structures with lower energy occupy higher specific gravity in practical application, the structures with lower energy are preferentially selected when the flexible dihedral angles are the same;
(2) using quantum chemical calculation software (such as PSI4), performing further structure optimization on the structure in step (1) by using high-precision quantum chemical method (such as B3LYP/6-31G (d)), and obtaining corresponding energy EQMAnd simultaneously optimizing the structures by using a force field needing to be detected to obtain the corresponding energy EMM；
(3) Linear fitting (python's scale module, _, R, _, Δ E = scaleQM,EMM) And obtaining Pearson correlation coefficient R and energy deviation dE of the two groups of data, if R is larger than a first threshold value and dE is smaller than a second threshold value, the invention preferably selects R to be larger than 0.7 and dE<2.0 kcal/mol (these two threshold criteria may be lowered or raised according to the user's specific requirements, and the criteria in the following steps are set as such), the process is terminated, and the force field parameters perform better in this molecule. Otherwise, entering the step (4);
(4) the molecules entering this step in step (3) are cut into smaller fragments, each fragment containing a flexible dihedral angle (rdkit. chem. rdmolops. fragmentonbonds () function applies to rdkit). And performing common dihedral angle scanning on the fragments, comparing quantum chemical data with force field data, and fitting dihedral angle parameters by using the obtained quantum chemical data to obtain new dihedral angle parameters for dihedral angles with poor performance (the correlation coefficient R of the dihedral angle data and the energy deviation dE of the energy deviation dE is less than 0.7 or more than 2.0 kilocalories/mole).
(5) Repeating the force field calculation in the step (2) by using the new dihedral angle parameter obtained in the step (4) to obtain new energy EMM'At this point in step (2) the previously calculated quantum chemical data EQM need not be recalculated, and then E is calculatedQMAnd EMM'And performing linear fitting to obtain a correlation coefficient R 'and an energy deviation dE' of the two groups of data. If R 'is greater than 0.7 and dE'<2.0 kcal/mol, the procedure was terminated and the newly fitted dihedral parameters performed better at this molecule. Otherwise, entering the step (6);
(6) the fitting process is performed by performing a normal dihedral scan of the whole molecule for the parameters still not well performing in steps (4) to (5). The dihedral angles that do not perform well in step (4) can be scanned first, followed by fitting of the dihedral angle parameters, calculation of the force field using the initially generated structure for the new fitting parameters, and the quantum chemistry results E that are present in step (2)QMBy comparison, if R is greater than 0.7 and dE<2.0 kcal/mol, and the process was terminated. And if not, scanning other flexible dihedral angles to fit relevant dihedral angle parameters.
The method for testing and fitting the parameters of the dihedral angle of the force field, provided by the invention, has the following technical advantages:
the method for detecting and fitting dihedral angle parameters of macromolecules provided by the invention saves more calculation amount than the common dihedral angle scanning of the whole molecule. By combining with the general process, the detection and fitting of the force field dihedral angle parameters with macromolecules are completed with lower computational resource consumption.
Drawings
FIG. 1 is a conventional general procedure for detecting and fitting macromolecules.
FIG. 2 is a flow chart of the present invention. The bottom left is a general method based on a whole molecule dihedral scan. In combination with the novel method of the invention, these steps need only be applied to dihedral angles whose appearance in the steps does not meet the set criteria.
Detailed Description
The specific technical scheme of the invention is described by combining the embodiment.
The flow shown in fig. 2:
taking as an example a macromolecule (SMILES: COC1= C (OCCCC2= NC3= CC 3[ N ]2C) C = C4N = CN = CC4= C1) having 6 flexible dihedral angles, 600 conformations need to be optimized if scanning with the usual whole molecule dihedral angle, the CPU time (the time required for a single CPU core to calculate) required for each structural optimization (quantum chemistry method using B3LYP/6-31g (d)) is 2 hours, the time for force field calculation and force field fitting is negligible with respect to the time for quantum chemistry calculation (in the following method, only the time for quantum chemistry calculation will be compared), so the total CPU time is 1200 hours.
According to the method designed by the present invention, 500 conformations were first generated using rdkit and 30 final conformations were determined based on structural screening. The amount of calculation required for this process is negligible.
These 30 conformations were then structurally optimized by quantum chemistry for 2 hours 30=60 hours force field method (using the disclosed GAFF2 force field) for negligible time. The CPU time required for this step is 60 hours.
Comparing the energy EQM of quantum chemistry with the energy EMM of the force field, a Pearson correlation coefficient R of 0.76 and a variance dE of 1.6 kcal/mol were obtained. This is in accordance with the criteria preset by the present invention. The performance of the detected force field meets the predetermined criterion without further fitting. The calculation amount of the whole method is 60 CPU time, which is greatly reduced compared with the traditional 1200 hours.
In order to compare the calculation amount of the following step, the present embodiment proceeds to the next step. This molecule was cut into 6 molecular fragments. Each performed from-180 degrees to 180 degrees and each performed at 15 degrees, such that 24 conformations were calculated for each molecular fragment, for a total of 24 x 6=144 conformations. The average CPU time required per molecular fragment calculation was 0.16 hours, so the total time required for this step was 144 x 0.16=23 hours. In this example, the molecular fragment quantum chemical data are used for fitting to obtain new parameters of six flexible dihedral angles. Applying the new parameters to the 30 conformations generated in the first step, compared to the quantum chemical data in the first step, the energy correlation coefficients and deviations were recalculated to 0.83 and 1.3kcal/mol, respectively. To this step, a total calculation time of 60+23=83 hours, much less than the usual 1200 hours required.
To demonstrate the overall process, this example selects the 2 relatively poor dihedral angles of the 6 dihedral angles to perform the dihedral angle scan of the whole molecule, and without considering the coupling, the required CPU time is 2 (number of dihedral angles) × 24 (number of conformations required per dihedral angle scan) × 2 hours =96 hours, and then performs the fitting of the two dihedral angle parameters. So that the total time required for this time was 96+60+23=179 hours.
In contrast to the above examples, the amount of computation required for the novel detection and fitting method of the present invention is much less than a typical dihedral scan of the entire molecule.
Claims (3)
1. A method of testing and fitting a force field dihedral angle parameter, comprising the steps of:
producing a representative series of conformations representing different angles of flexible dihedral in the molecule; comparing the force field with the quantum chemical method for the structures, if the force field meets the standard, determining that the force field parameters are satisfactory in performance, and ending the process; if the two-dimensional data do not meet the standard, further cutting the macromolecules into molecular fragments only containing one flexible dihedral angle, scanning the dihedral angle, comparing the quantum chemical result of each flexible dihedral angle with the force field result, finding out the flexible dihedral angle which does not meet the standard, and fitting the parameters of the flexible dihedral angle; after obtaining new dihedral angle parameters, returning the new dihedral angle parameters to a series of structures of the initially generated whole molecules for verification, if the new dihedral angle parameters meet the standard, finishing the whole process, and finishing detecting and fitting the dihedral angle parameters with poor performance; if not, a soft dihedral with poor performance is scanned across the molecule.
2. The method of claim 1 for testing and fitting force field dihedral angle parameters, specifically comprising the steps of:
(1) for a macromolecule, 500 conformations are firstly generated for each molecule by using rdkit, the molecules are structurally optimized by using the UFF force field carried by the rdkit, and the angle of each flexible dihedral angle of each structure is calculated; selecting 30 structures according to the angle distribution of the flexible dihedral angle, covering different areas from-180 degrees to 180 degrees, and preferentially selecting the structure with lower energy;
(2) using quantum chemical calculation software to further optimize the structure in the step (1) by using a high-precision quantum chemical method to obtain corresponding energy EQM, and simultaneously optimizing the structures by using a force field needing to be detected to obtain corresponding energy EMM;
(3) performing linear fitting on the two groups of energy obtained in the step (2) by taking molecules as units to obtain Pearson correlation coefficients R and energy deviation dE of the two groups of data, and if R is greater than a first threshold value and dE is less than a second threshold value, stopping the process, wherein the force field parameters are better represented by the molecules; otherwise, entering the step (4);
(4) cutting the molecules entering this step of step (3) into smaller pieces, each piece comprising a flexible dihedral angle; performing common dihedral angle scanning on the fragments, comparing quantum chemical data with force field data, and fitting dihedral angle parameters by using the obtained quantum chemical data to obtain new dihedral angle parameters for the dihedral angles with poor performance;
the performance is not good, namely the correlation coefficient R of the two is smaller than a first threshold value or the energy deviation dE is larger than a second threshold value;
(5) repeating the force field calculation in the step (2) by using the new dihedral angle parameter obtained in the step (4) to obtain new energy EMM'; at the moment, the quantum chemical data EQM calculated in the step (2) does not need to be calculated repeatedly, and then the EQM and the EMM ' are subjected to linear fitting to obtain a correlation coefficient R ' and an energy deviation dE ' of two groups of data; if R 'is greater than the first threshold and dE' is less than the second threshold, terminating the process, where the newly fitted dihedral angle parameter performs better; otherwise, entering the step (6);
(6) performing a fitting process on the parameters which still do not perform well in the steps (4) to (5) by performing a common dihedral angle scan on the whole molecule; scanning dihedral angles which do not well appear in the step (4), then performing dihedral angle parameter fitting, calculating a force field by using an initially generated structure for new fitting parameters, comparing the force field with the existing quantum chemistry result EQM in the step (2), and if R is greater than a first threshold value and dE is less than a second threshold value, terminating the process; and if not, scanning other flexible dihedral angles to fit relevant dihedral angle parameters.
3. A method of testing and fitting a force field dihedral angle parameter as claimed in claim 2, wherein said first threshold is 0.7 and said second threshold is 2.0 kcal/mol.
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