Accelerated Molecular Dynamics Simulation for Helical Proteins Folding in Explicit Water

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.

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

“…MD excels in focusing on the dynamical aspects of a given protein or enzyme in relation to its function. Applications include, for instance, estimation of affinities ∆ b G (the standard Gibbs free energy of binding) of ligands for proteins using the so-called free energy perturbation (FEP) methods [40], the inclusion of charge fluctuations in constant pH AAMD [41], folding of small proteins [42], and the simulation of ion channels [43]. Additional examples are also listed in the recent reviews by Cavalli and collaborators [44] and Hollingsworth and Dror [45].…”

Structure-Based Virtual Screening and Biochemical Validation to Discover a Potential Inhibitor of the SARS-CoV-2 Main Protease

“…Molecular dynamics simulation techniques have been used to explore bio-macromolecular interactions and evolved as a state-of-the-art technique in recent years. 33 MD simulations have been used successfully to explore the complex protein folding pathways, 34 protein–ligand binding, 35 − 37 nucleic acid structure and interactions, 38 − 41 and macromolecular mechanisms. 40 , 41 In the present study, we performed MD simulations on the docked structures to explore the binding of the ligand with protein as a function of time in explicit solvent conditions (to mimic the biological environment).…”

Promising Acyclovir and its derivatives to inhibit the protease of SARS-CoV-2: Molecular Docking and Molecular Dynamics simulations

“…Different trajectories like root mean square deviation (RMSD), root mean square fluctuation (RMSF) and number of hydrogen bonds ware determined through MD simulations. (Duan et al, 2019;Skjevik et al, 2015;Srivastava & Sastry, 2012;Wang et al, 2019;Xu, Sun, Li, Wang, & Hou, 2013) The RMSD curve is obtained from correlating time with the deviations to understand the stability of the complexes in comparison of the protease alone and can be determined based on the following equation. (Alexandrescu, Snyder, & Abildgaard, 2001;Bruschweiler, 2003) Where N is the number of atoms, X m , Y m , Z m are the Cartesian coordinates of the initial structure and X l , Y l , Z l are the Cartesian coordinates of trajectory at frame t.…”