Mechanics of channel gating of the nicotinic acetylcholine receptor
文献类型：期刊论文
| 作者 | Liu, Xinli1; Xu, Yechun2 ; Li, Honglin2; Wang, Xicheng1; Jiang, Hualiang2,3; Barrantes, Francisco J.4,5
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| 刊名 | PLOS COMPUTATIONAL BIOLOGY
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| 出版日期 | 2008-01 |
| 卷号 | 4期号:1 |
| ISSN号 | 1553-7358 |
| DOI | 10.1371/journal.pcbi.0040019 |
| 文献子类 | Article |
| 英文摘要 | The nicotinic acetylcholine receptor ( nAChR) is a key molecule involved in the propagation of signals in the central nervous system and peripheral synapses. Although numerous computational and experimental studies have been performed on this receptor, the structural dynamics of the receptor underlying the gating mechanism is still unclear. To address the mechanical fundamentals of nAChR gating, both conventional molecular dynamics (CMD) and steered rotation molecular dynamics (SRMD) simulations have been conducted on the cryo-electron microscopy (cryo-EM) structure of nAChR embedded in a dipalmitoylphosphatidylcholine ( DPPC) bilayer and water molecules. A 30-ns CMD simulation revealed a collective motion amongst C-loops, M1, and M2 helices. The inward movement of C-loops accompanying the shrinking of acetylcholine (ACh) binding pockets induced an inward and upward motion of the outer beta-sheet composed of beta 9 and beta 10 strands, which in turn causes M1 and M2 to undergo anticlockwise motions around the pore axis. Rotational motion of the entire receptor around the pore axis and twisting motions among extracellular (EC), transmembrane (TM), and intracellular MA domains were also detected by the CMD simulation. Moreover, M2 helices undergo a local twisting motion synthesized by their bending vibration and rotation. The hinge of either twisting motion or bending vibration is located at the middle of M2, possibly the gate of the receptor. A complementary twisting-to-open motion throughout the receptor was detected by a normal mode analysis (NMA). To mimic the pulsive action of ACh binding, nonequilibrium MD simulations were performed by using the SRMD method developed in one of our laboratories. The result confirmed all the motions derived from the CMD simulation and NMA. In addition, the SRMD simulation indicated that the channel may undergo an open-close (O <-> C) motion. The present MD simulations explore the structural dynamics of the receptor under its gating process and provide a new insight into the gating mechanism of nAChR at the atomic level. |
| WOS关键词 | MOLECULAR-DYNAMICS SIMULATIONS ; NORMAL-MODE ANALYSIS ; PARTICLE MESH EWALD ; GATED ION-CHANNEL ; TRANSMEMBRANE DOMAIN ; SINGLE-PARAMETER ; PORE DIMENSIONS ; LINING RESIDUES ; BINDING ; PROTEINS |
| WOS研究方向 | Biochemistry & Molecular Biology ; Mathematical & Computational Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000255407500005 |
| 出版者 | PUBLIC LIBRARY SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273085]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Wang, Xicheng |
| 作者单位 | 1.Dalian Univ Technol, Dept Mech Engn, Dalian, Liaoning, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 200031, Peoples R China; 3.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China; 4.UNESCO Chair Biophys & Mol Neurobiol, Bahia Blanca, Buenos Aires, Argentina; 5.Inst Invest Bioquim, Bahia Blanca, Buenos Aires, Argentina |
| 推荐引用方式 GB/T 7714 | Liu, Xinli,Xu, Yechun,Li, Honglin,et al. Mechanics of channel gating of the nicotinic acetylcholine receptor[J]. PLOS COMPUTATIONAL BIOLOGY,2008,4(1). |
| APA | Liu, Xinli,Xu, Yechun,Li, Honglin,Wang, Xicheng,Jiang, Hualiang,&Barrantes, Francisco J..(2008).Mechanics of channel gating of the nicotinic acetylcholine receptor.PLOS COMPUTATIONAL BIOLOGY,4(1). |
| MLA | Liu, Xinli,et al."Mechanics of channel gating of the nicotinic acetylcholine receptor".PLOS COMPUTATIONAL BIOLOGY 4.1(2008). |
入库方式： OAI收割
来源：上海药物研究所
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