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

文献类型：期刊论文

作者Peng, Cheng1,2; Wang, Jinan2; Shi, Yulong1,2; Xu, Zhijian1,2; Zhu, Weiliang1,2,3
刊名JOURNAL OF CHEMICAL THEORY AND COMPUTATION
出版日期2021-01-12
卷号17期号:1页码:13-28
ISSN号1549-9618
DOI10.1021/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.
WOS关键词FREE-ENERGY LANDSCAPE ; ADENYLATE KINASE ; HIV-1 PROTEASE ; SUBSTRATE-BINDING ; MONTE-CARLO ; CRYSTAL-STRUCTURES ; C-ABL ; TRANSITIONS ; SIMULATIONS ; METADYNAMICS
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研究方向Chemistry ; Physics
语种英语
WOS记录号WOS:000610984100003
出版者AMER CHEMICAL SOC
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.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, CAS Key Lab Receptor Res Drug Discovery & Design, Shanghai Inst Mat Med, Shanghai 201203, 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.

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来源：上海药物研究所

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