Increasing the Sampling Efficiency of Protein Conformational Change by Combining a Modified Replica Exchange Molecular Dynamics and Normal Mode Analysis.

Understanding conformational change at an atomic level is significant when determining a protein functional mechanism. Replica exchange molecular dynamics (REMD) is a widely used enhanced sampling method to explore protein conformational space. However, REMD with an explicit solvent model requires huge computational resources, immensely limiting its application. In this study, a variation of parallel tempering metadynamics (PTMetaD) with the omission of solvent-solvent interactions in exchange attempts and the use of low-frequency modes calculated by normal-mode analysis (NMA) as collective variables (CVs), namely ossPTMetaD, is proposed with the aim to accelerate MD simulations simultaneously in temperature and geometrical spaces. For testing the performance of ossPTMetaD, five protein systems with diverse biological functions and motion patterns were selected, including large-scale domain motion (AdK), flap movement (HIV-1 protease and BACE1), and DFG-motif flip in kinases (p38α and c-Abl). The simulation results showed that ossPTMetaD requires much fewer numbers of replicas than temperature REMD (T-REMD) with a reduction of ∼70% to achieve a similar exchange ratio. Although it does not obey the detailed balance condition, ossPTMetaD provides consistent results with T-REMD and experimental data. The high accessibility of the large conformational change of protein systems by ossPTMetaD, especially in simulating the very challenging DFG-motif flip of protein kinases, demonstrated its high efficiency and robustness in the characterization of the large-scale protein conformational change pathway and associated free energy profile.