How does Huperzine A enter and leave the binding gorge of acetylcholinesterase? Steered molecular dynamics simulations
文献类型：期刊论文
| 作者 | Xu, YC ; Shen, JH; Luo, XM; Silman, I; Sussman, JL; Chen, KX; Jiang, HL
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| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
 |
| 出版日期 | 2003-09-17 |
| 卷号 | 125期号:37页码:11340-11349 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/ja029775t |
| 文献子类 | Article |
| 英文摘要 | The entering and leaving processes of Huperzine A (HupA) binding with the long active-site gorge of Torpedo californica acetylcholinesterase (TcAChE) have been investigated by using steered molecular dynamics simulations. The analysis of the force required along the pathway shows that it is easier for HupA to bind to the active site of AChE than to disassociate from it, which for the first time interprets at the atomic level the previous experimental result that unbinding process of HupA is much slower than its binding process to AChE. The direct hydrogen bonds, water bridges, and hydrophobic interactions were analyzed during two steered molecular dynamics (SMD) simulations. Break of the direct hydrogen bond needs a great pulling force. The steric hindrance of bottleneck might be the most important factor to produce the maximal rupture force for HupA to leave the binding site but it has a little effect on the binding process of HupA with AChE. Residue Asp72 forms a lot of water bridges with HupA leaving and entering the AChE binding gorge, acting as a clamp to take out HupA from or put HupA into the active site. The flip of the peptide bond between Gly117 and Gly118 has been detected during both the conventional MD and SMD simulations. The simulation results indicate that this flip phenomenon could be an intrinsic property of AChE and the Gly117-Gly118 peptide bond in both HupA bound and unbound AChE structures tends to adopt the native enzyme structure. At last, in a vacuum the rupture force is increased up to 1500 pN while in water solution the greatest rupture force is about 800 pN, which means water molecules in the binding gorge act as lubricant to facilitate HupA entering or leaving the binding gorge. |
| WOS关键词 | ACTIVE-SITE GORGE ; LIGAND-BINDING ; MOUSE ACETYLCHOLINESTERASE ; TORPEDO-CALIFORNICA ; WATER-MOLECULES ; FORCE ; PROTEINS ; FASCICULIN ; MECHANISM ; RESIDUES |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000185341800056 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/274183]  |
| 专题 | 新药研究国家重点实验室 中科院受体结构与功能重点实验室 |
| 通讯作者 | Shen, JH |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Met Med, Shanghai Inst Biol Sci, State Key Lab Drug Res,Ctr Drug Discovery & Design, Shanghai 201203, Peoples R China 2.Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel |
| 推荐引用方式 GB/T 7714 | Xu, YC,Shen, JH,Luo, XM,et al. How does Huperzine A enter and leave the binding gorge of acetylcholinesterase? Steered molecular dynamics simulations[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2003,125(37):11340-11349. |
| APA | Xu, YC.,Shen, JH.,Luo, XM.,Silman, I.,Sussman, JL.,...&Jiang, HL.(2003).How does Huperzine A enter and leave the binding gorge of acetylcholinesterase? Steered molecular dynamics simulations.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,125(37),11340-11349. |
| MLA | Xu, YC,et al."How does Huperzine A enter and leave the binding gorge of acetylcholinesterase? Steered molecular dynamics simulations".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 125.37(2003):11340-11349. |
入库方式： OAI收割
来源：上海药物研究所
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