Long Route or Shortcut? A Molecular Dynamics Study of Traffic of Thiocholine within the Active-Site Gorge of Acetylcholinesterase
文献类型：期刊论文
| 作者 | Xu, Yechun1,2,5 ; Colletier, Jacques-Philippe4; Weik, Martin4; Qin, Guangrong2; Jiang, Hualiang2,3; Silman, Israel5; Sussman, Joel L.1
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| 刊名 | BIOPHYSICAL JOURNAL
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| 出版日期 | 2010-12-15 |
| 卷号 | 99期号:12页码:4003-4011 |
| ISSN号 | 0006-3495 |
| DOI | 10.1016/j.bpj.2010.10.047 |
| 文献子类 | Article |
| 英文摘要 | The principal role of acetylcholinesterase is termination of nerve impulse transmission at cholinergic synapses, by rapid hydrolysis of the neurotransmitter acetylcholine to acetate and choline. Its active site is buried at the bottom of a deep and narrow gorge, at the rim of which is found a second anionic site, the peripheral anionic site. The fact that the active site is so deeply buried has raised cogent questions as to how rapid traffic of substrate and products occurs in such a confined environment. Various theoretical and experimental approaches have been used to solve this problem. Here, multiple conventional molecular dynamics simulations have been performed to investigate the clearance of the product, thiocholine, from the active-site gorge of acetylcholinesterase. Our results indicate that thiocholine is released from the peripheral anionic site via random pathways, while three exit routes appear to be favored for its release from the active site, namely, along the axis of the active-site gorge, and through putative back- and side-doors. The back-door pathway is that via which thiocholine exits most frequently. Our results are in good agreement with kinetic and kinetic-crystallography studies. We propose the use of multiple molecular dynamics simulations as a fast yet accurate complementary tool in structural studies of enzymatic trafficking. |
| WOS关键词 | PARTICLE MESH EWALD ; MOUSE ACETYLCHOLINESTERASE ; X-RAY ; ELECTROSTATIC POTENTIALS ; AROMATIC RESIDUES ; SIMULATION ; MECHANISM ; SUBSTRATE ; INHIBITION ; BINDING |
| 资助项目 | National Natural Science Foundation of China[20720102040] ; State Key Program of Basic Research of China[2009CB918501] ; National ST Major Project[2009ZX09501-001] ; National ST Major Project[2009ZX09301-001] ; Delegation Generale pour l'Armement[DGA-REI 2009-34-0023] ; Agence Nationale de la Recherche[ANR-09-BLAN-0192-04] ; European Commission[031220] ; "Teach-SG" Project[ISSG-CT-2007-037198] ; Kimmelman Center for Biomolecular Structure and Assembly[00000000] ; Benoziyo Center for Neurosciences[00000000] ; Divadol Foundation[00000000] ; Nalvyco Foundation[00000000] ; Bruce Rosen Foundation[00000000] ; Jean and Julia Goldwurm Memorial Foundation[00000000] ; Neuman Foundation[00000000] ; Kalman and Ida Wolens Foundation[00000000] ; Erwin Pearl[00000000] ; Computer Network Information Center of the Chinese Academy of Sciences[00000000] ; Shanghai:Supercomputing Center[00000000] ; Chinese Academy of Sciences[00000000] |
| WOS研究方向 | Biophysics |
| 语种 | 英语 |
| WOS记录号 | WOS:000285438900024 |
| 出版者 | CELL PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278688]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Xu, Yechun |
| 作者单位 | 1.Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 200031, Peoples R China; 3.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China; 4.Inst Biol Struct, Lab Biophys Mol, Grenoble, France; 5.Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel |
| 推荐引用方式 GB/T 7714 | Xu, Yechun,Colletier, Jacques-Philippe,Weik, Martin,et al. Long Route or Shortcut? A Molecular Dynamics Study of Traffic of Thiocholine within the Active-Site Gorge of Acetylcholinesterase[J]. BIOPHYSICAL JOURNAL,2010,99(12):4003-4011. |
| APA | Xu, Yechun.,Colletier, Jacques-Philippe.,Weik, Martin.,Qin, Guangrong.,Jiang, Hualiang.,...&Sussman, Joel L..(2010).Long Route or Shortcut? A Molecular Dynamics Study of Traffic of Thiocholine within the Active-Site Gorge of Acetylcholinesterase.BIOPHYSICAL JOURNAL,99(12),4003-4011. |
| MLA | Xu, Yechun,et al."Long Route or Shortcut? A Molecular Dynamics Study of Traffic of Thiocholine within the Active-Site Gorge of Acetylcholinesterase".BIOPHYSICAL JOURNAL 99.12(2010):4003-4011. |
入库方式： OAI收割
来源：上海药物研究所
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