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

doi:10.1021/acs.jctc.0c00592

	Increasing the Sampling Efficiency of Protein Conformational Change by Combining a Modified Replica Exchange Molecular Dynamics and Normal Mode Analysis
	Peng, Cheng 1,2; Wang, Jinan 1; Shi, Yulong 1,2; Xu, Zhijian 1,2; Zhu, Weiliang 1,2,3
刊名	JOURNAL OF CHEMICAL THEORY AND COMPUTATION
	2021-01-12
卷号	17 期号:1 页码:13-28
ISSN号	1549-9618
DOI	10.1021/acs.jctc.0c00592
通讯作者	Zhu, Weiliang(wlzhu@simm.ac.cn)
英文摘要	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 (p38 alpha and c-Abl). The simulation results showed that ossPTMetaD requires much fewer numbers of replicas than temperature REMD (T-REMD) with a reduction of similar to 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.
资助项目	National Key Research and Development Program[2016YFA0502301] ; National Natural Science Foundation of China[81573350] ; National Natural Science Foundation of China[81872797] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002]
WOS关键词	FREE-ENERGY LANDSCAPE ; ADENYLATE KINASE ; HIV-1 PROTEASE ; SUBSTRATE-BINDING ; MONTE-CARLO ; CRYSTAL-STRUCTURES ; C-ABL ; TRANSITIONS ; SIMULATIONS ; METADYNAMICS
WOS研究方向	Chemistry ; Physics
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000610984100003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295827]
专题	中国科学院上海药物研究所
通讯作者	Zhu, Weiliang
作者单位	1.Chinese Acad Sci, CAS Key Lab Receptor Res Drug Discovery & Design, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Qingdao Natl Lab Marine Sci & Technol, Open Studio Druggabil Res Marine Lead Cpds, Qingdao 266237, Shandong, Peoples R China
推荐引用方式 GB/T 7714	Peng, Cheng,Wang, Jinan,Shi, Yulong,et al. Increasing the Sampling Efficiency of Protein Conformational Change by Combining a Modified Replica Exchange Molecular Dynamics and Normal Mode Analysis[J]. JOURNAL OF CHEMICAL THEORY AND COMPUTATION,2021,17(1):13-28.
APA	Peng, Cheng,Wang, Jinan,Shi, Yulong,Xu, Zhijian,&Zhu, Weiliang.(2021).Increasing the Sampling Efficiency of Protein Conformational Change by Combining a Modified Replica Exchange Molecular Dynamics and Normal Mode Analysis.JOURNAL OF CHEMICAL THEORY AND COMPUTATION,17(1),13-28.
MLA	Peng, Cheng,et al."Increasing the Sampling Efficiency of Protein Conformational Change by Combining a Modified Replica Exchange Molecular Dynamics and Normal Mode Analysis".JOURNAL OF CHEMICAL THEORY AND COMPUTATION 17.1(2021):13-28.