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Unveiling conformational dynamics changes of H-Ras induced by mutations based on accelerated molecular dynamics

文献类型：期刊论文

作者Chen, Jianzhong1; Wang, Wei1; Pang, Laixue1; Zhu, Weiliang2
刊名PHYSICAL CHEMISTRY CHEMICAL PHYSICS
出版日期2020-10-07
卷号22期号:37页码:21238-21250
ISSN号1463-9076
DOI10.1039/d0cp03766d
通讯作者Chen, Jianzhong(jzchen@sdjtu.edu.cn) ; Zhu, Weiliang(wlzhu@simm.ac.cn)
英文摘要Uncovering molecular basis with regard to the conformational change of two switches I and II in the GppNHp (GNP)-bound H-Ras is highly significant for the understanding of Ras signaling. For this purpose, accelerated molecular dynamics (aMD) simulations and principal component (PC) analysis are integrated to probe the effect of mutations G12V, T35S and Q61K on conformational transformation between two switches of the GNP-bound H-Ras. The RMSF and cross-correlation analyses suggest that three mutations exert a vital effect on the flexibility and internal dynamics of two switches in the GNP-bound H-Ras. The results stemming from PC analysis indicate that two switches in the GNP-bound WT H-Ras tend to form a closed state in most conformations, while those in the GNP-bound mutated H-Ras display transformation between different states. This conclusion is further supported by free energy landscapes constructed by using the distances of residues 12 away from 35 and 35 away from 61 as reaction coordinates and different experimental studies. Interaction scanning is performed on aMD trajectories and the information shows that conformational transformations of two switches I and II induced by mutations extremely affect the GNP-residue interactions. Meanwhile, the scanning results also signify that residues G15, A18, F28, K117, A146 and K147 form stable contacts with GNP, while residues D30, E31, Y32, D33, P34 and E62 in two switches I and II produce unstable contacts with GNP. This study not only reveals dynamic behavior changes of two switches in H-Ras induced by mutations, but also unveils general principles and mechanisms with regard to functional conformational changes of H-Ras.
WOS关键词FREE-ENERGY PERTURBATION ; COMPLEX-FORMATION ; SIGNAL-TRANSDUCTION ; STRUCTURAL BASIS ; BINDING DOMAIN ; SWITCH-II ; PROTEIN ; SIMULATIONS ; GTP ; AMBER
资助项目National Key Research and Development Program[2016YFA0502301] ; National Natural Science Foundation of China[21403283] ; National Natural Science Foundation of China[81573350] ; Shandong Provincial Natural Science Foundation[ZR2017MA040] ; Key Research and Development Project of Shandong Province[2018GSF121014] ; Key Research and Development Project of Shandong Province[2019GGX102050]
WOS研究方向Chemistry ; Physics
语种英语
出版者ROYAL SOC CHEMISTRY
WOS记录号WOS:000573875300024
源URL[http://119.78.100.183/handle/2S10ELR8/291293]  
专题中国科学院上海药物研究所
通讯作者Chen, Jianzhong; Zhu, Weiliang
作者单位1.Shandong Jiaotong Univ, Sch Sci, Jinan 250357, Peoples R China
2.Chinese Acad Sci, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Jianzhong,Wang, Wei,Pang, Laixue,et al. Unveiling conformational dynamics changes of H-Ras induced by mutations based on accelerated molecular dynamics[J]. PHYSICAL CHEMISTRY CHEMICAL PHYSICS,2020,22(37):21238-21250.
APA Chen, Jianzhong,Wang, Wei,Pang, Laixue,&Zhu, Weiliang.(2020).Unveiling conformational dynamics changes of H-Ras induced by mutations based on accelerated molecular dynamics.PHYSICAL CHEMISTRY CHEMICAL PHYSICS,22(37),21238-21250.
MLA Chen, Jianzhong,et al."Unveiling conformational dynamics changes of H-Ras induced by mutations based on accelerated molecular dynamics".PHYSICAL CHEMISTRY CHEMICAL PHYSICS 22.37(2020):21238-21250.

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来源：上海药物研究所

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