Accelerating The Binding/release Process Between Protein And Ligands Based On Multiple Independent Simulations And The Influence Of Force Field On Protein Structure Sampling

The study of the conformation of biological macromolecules has always been a very important field in structural biology.With the development of science and technology and the continuous updating of research methods,there are now a wealth of research tools to choose.These research tools can be divided into two categories.One is the experimental methods such as X-ray crystal diffraction,nuclear magnetic resonance technology,and cryo-electron microscopy technology.The other are computer simulation methods such as molecular dynamics simulation(MD).With the continuous improvement of computing power and the accuracy of molecular force fields,MD has shown great advantages in studying the binding and release pathways of biological macromolecules.However,when the system to be studied is large,the time scale and length scale of the simulation is still a big challenge.In this paper,an enhanced sampling method based on multiple independent molecular dynamics simulations(MIMD)is developed to study the binding and dissociation process of ligands.We chose adenylate kinase adenylate kinase(AdK)as the research system for three reasons.Firstly,AdK is a model system in macromolecular simulation.There are many experimental data available to facilitate the comparison between simulation results and experiments.Secondly,the ligand binding and dissociation process of the AdK system has obtained sufficient data in a large number of molecular simulations in the past.The effect of our method can be seen by direct comparison with conventional molecular simulations.Finally,the size of the AdK system is moderate,and the time scale and length scale of the simulation is reasonable.Based on the MIMD simulation results of the AdK system,compared with conventional molecular dynamics simulation,a more adequate sampling of the ligand binding and dissociation process can be obtained.In another system,our research object is the bacteriophage T4 lysosome(T4L).T4L is also a model system.The main feature of its structure is that the opening and closing of the C-terminal and T-terminal domain pockets are closely related to their biological activity.The two ends of the protein pocket are connected by a helices.This protein contains 164 amino acids,a modest size that is convenient for research.In order to test the accuracy of sampling,we tried multiple combinations of force fields and water models.At the same time,we compare the simulated results with the experimental data of small angle X-ray scattering(SAXS).After preliminary research,it is found that RSFF2+/TIP4P-D and A99SB-disp may be good choices of force fields and water models.