Study On Accelerated Molecular Dynamics For Protein Folding Under Explicit Solvent Model

Almost all life activities are performed by proteins,which are active only when they are folded into native structures.Protein folding errors can cause a range of diseases,such as Parkinson's disease,Alzheimer's disease,mad cow disease,and Gul's disease.Protein folding is an important subject of biophysics in the 21 st century.It is very important to understand the folding pathway and folding mechanism of protein.Molecular dynamics simulation has been developed for decades,and has been widely used to study biophysics,chemistry,materials and so on.The information of conformation evolution of proteins and other biological macromolecules over time can be obtained by molecular dynamics simulation.The molecular dynamics simulation method can be used to study and quantitatively describe the protein system at molecular level.Therefore,molecular dynamics simulation has become a powerful tool for studying the structural and functional basis of proteins.However,the efficiency of traversing the phase space sampling is still one of the problems that need to be solved by the molecular dynamic simulation method.Recently,J.A.McCammon has developed methods to accelerate molecular dynamics.The acceleration of the molecular dynamics is to add a potential energy on the basis of the original potential energy to reduce the barrier height,and the probability of the system falling into the local minimum is reduced and the transition rate between the low energy is improved,so that the efficiency of traversing the sampling is increased.In this study,we examined the folding processes of eight helical proteins(2I9M,TC5 B,1WN8,1V4 Z,1HO2,1HLL,2KFE and 1YYB)at room temperature using the explicit solvent model under the AMBER14 SB force field with the accelerated molecular dynamics(AMD)and traditional molecular dynamics(MD),respectively.We analyzed and compared the simulation results obtained by these two methods based on several aspects,such as root mean square deviation(RMSD),native contacts,cluster analysis,folding snapshots,free energy landscape and the evolution of the radius of gyration,which show that these eight proteins were successfully and consistently folded into the corresponding native structures by AMD simulations carried out at room temperature.By contrast,these stable folding structures were not found when the traditional molecular dynamics(MD)simulation is used.At the same time,the influence of high temperatures(350 K,400 K and 450 K)is also further investigated.Study found that the simulation efficiency of AMD is higher than that of MD simulations,regardless of the temperature.Of these temperatures,300 K is the most suitable temperature for protein folding for all systems.To further investigate the efficiency of AMD,another trajectory was simulated for eight proteins with the same linear structure but different random seeds at 300 K.Both AMD trajectories reach the correct folded structures.Our result clearly shows that AMD simulation are a highly efficient and reliable method for the study of protein folding.The paper is divided into four chapters.The first chapter describes the background of the research.The second chapter is about the theory and method,including the basic principle of molecular dynamics simulation,the integral algorithm of molecular dynamics simulation,the molecular force field and accelerated molecular dynamics.The third chapter mainly introduces the content of my research.Chapter three is divided into four parts: accelerating molecular dynamics simulation,preparation of molecular dynamics simulation system,results and discussion,conclusion.The focus is on the detailed description of the third part of the results and discussion,including eight parts: root mean square deviation(RMSD),native contact,cluster analysis,protein folding process,free energy landscape analysis,radius of gyration,the effect of different high temperature and multiple-trajectory result.All the results show that accelerated analytical dynamics can fold protein from linear structure to natural or approximate natural structure more accurately and quickly than traditional molecular dynamics.The fourth chapter is a summary and prospect,which is mainly a brief summary of the work done by ourselves and the application of accelerated molecular dynamics simulation in the future.In view of the fact that the folding time is only considered to be a small number of proteins,we have some limitations in the study of protein folding using accelerated molecular dynamics simulation under the explicit solvent model.With the development of accelerated molecular dynamics and the improvement of computer level,it is believed that accelerated molecular dynamics can be used to study larger protein systems in the future,and even more can be used to simulate the complex of large proteins and small molecules.