Accelerated Molecular Dynamics Simulation for Helical Proteins Folding in Explicit Water.

Lili Duan,Xiaona Guo,Yalong Cong,John Z H Zhang,Yuchen Li,Guoqiang Feng

doi:10.3389/fchem.2019.00540

Abstract

In this study, we examined the folding processes of eight helical proteins (2I9M, TC5B, 1WN8, 1V4Z, 1HO2, 1HLL, 2KFE, and 1YYB) at room temperature using the explicit solvent model under the AMBER14SB 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 showed that these eight proteins were successfully and consistently folded into the corresponding native structures by AMD simulations carried out at room temperature. In addition, the folding occurred in the range of 40~180 ns after starting from the linear structures of the eight proteins at 300 K. By contrast, these stable folding structures were not found when the traditional molecular dynamics (MD) simulation was used. At the same time, the influence of high temperatures (350, 400, 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 reached the correct folded structures. Our result clearly shows that AMD simulation are a highly efficient and reliable method for the study of protein folding.

Highlights

Protein misfolding can cause a series of diseases, such as Parkinson’s disease, Alzheimer’s disease, mad cow disease, and Gusher’s disease (Dobson, 1999; Slepoy et al, 2001; Muchowski, 2002; Cohen and Kelly, 2003; Chiti and Dobson, 2006)
We perform ab initio folding for eight proteins (2I9M, TC5B, 1WN8, 1V4Z, 1HO2, 1HLL, 2KFE, and 1YYB) using accelerated molecular dynamics (AMD) simulations and traditional molecular dynamics (MD) simulation at different temperatures (300, 350, 400, and 450 K) in explicit water
The native contacts analysis shows that the fraction of the native contacts of these eight proteins in AMD simulation are clearly higher than those in the MD simulation, indicating that the structures generated from AMD simulations are more consistent with the native states

Summary

Introduction

Protein misfolding can cause a series of diseases, such as Parkinson’s disease, Alzheimer’s disease, mad cow disease, and Gusher’s disease (Dobson, 1999; Slepoy et al, 2001; Muchowski, 2002; Cohen and Kelly, 2003; Chiti and Dobson, 2006). With the increase in computing power, all-atom molecular dynamics (MD) simulations have become a popular tool for the studies of protein folding for many researchers (Duan and Kollman, 1998; Brooks, 2002; Daggett, 2002; Eleftheriou et al, 2006; Yoda et al, 2007; Hua et al, 2008; Nelson and Grishin, 2008; Lindorff-Larsen et al, 2011; Nguyen et al, 2014; Weber et al, 2014; Li et al, 2015; Bernhardt et al, 2016; Perez et al, 2016; Schwantes et al, 2016). Some biological important processes such as enzyme catalysis, protein-ligand binding, signal transduction, and allosteric regulation require the time-scales ranging from microsecond to millisecond (Markwick and McCammon, 2011)

Methods

Results

Conclusion