Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations

doi:10.1038/s41598-017-03088-y

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	Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations
	Cheng, Shanmei; Song, Wanling; Yuan, Xiaojing; Xu, Yechun
刊名	SCIENTIFIC REPORTS
	2017-06-12
卷号	7
ISSN号	2045-2322
DOI	10.1038/s41598-017-03088-y
文献子类	Article
英文摘要	Acetylcholinesterase, with a deep, narrow active-site gorge, attracts enormous interest due to its particularly high catalytic efficiency and its inhibitors used for treatment of Alzheimer's disease. To facilitate the massive pass-through of the substrate and inhibitors, "breathing" motions to modulate the size of the gorge are an important prerequisite. However, the molecular mechanism that governs such motions is not well explored. Here, to systematically investigate intrinsic motions of the enzyme, we performed microsecond molecular dynamics simulations on the monomer and dimer of Torpedo californica acetylcholinesterase (TcAChE) as well as the complex of TcAChE bound with the drug E2020. It has been revealed that protein-ligand interactions and dimerization both keep the gorge in bulk, and opening events of the gorge increase dramatically compared to the monomer. Dynamics of three subdomains, S3, S4 and the Omega-loop, are tightly associated with variations of the gorge size while the dynamics can be changed by ligand binding or protein dimerization. Moreover, high correlations among these subdomains provide a basis for remote residues allosterically modulating the gorge motions. These observations are propitious to expand our understanding of protein structure and function as well as providing clues for performing structure-based drug design.
资助项目	National Key RD Project[2016YFA0502301] ; National Natural Science Foundation of China[81422047] ; National Natural Science Foundation of China[81661148046] ; National Supercomputer Center in Guangzhou (Tianhe-2)[00000000]
WOS关键词	ACTIVE-SITE GORGE ; PARTICLE MESH EWALD ; TORPEDO-CALIFORNICA ; SIGNAL-TRANSDUCTION ; PROTEIN-KINASE ; BINDING ; CHOLINESTERASES ; SPECIFICITY ; MECHANISM ; DIFFUSION
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000403081900010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272611]
专题	药物发现与设计中心
通讯作者	Xu, Yechun
作者单位	Chinese Acad Sci, CAS Key Lab Receptor Res, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Cheng, Shanmei,Song, Wanling,Yuan, Xiaojing,et al. Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations[J]. SCIENTIFIC REPORTS,2017,7.
APA	Cheng, Shanmei,Song, Wanling,Yuan, Xiaojing,&Xu, Yechun.(2017).Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations.SCIENTIFIC REPORTS,7.
MLA	Cheng, Shanmei,et al."Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations".SCIENTIFIC REPORTS 7(2017).