Dynamic mechanism of E2020 binding to acetylcholinesterase: A steered molecular dynamics simulation

doi:10.1021/jp0552877

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Dynamic mechanism of E2020 binding to acetylcholinesterase: A steered molecular dynamics simulation
	Niu, CY ; Xu, YC; Xu, Y ; Luo, XM; Duan, WH; Silman, I ; Sussman, JL ; Zhu, WL; Chen, KX; Shen, JH
刊名	JOURNAL OF PHYSICAL CHEMISTRY B
	2005-12-15
卷号	109 期号:49 页码:23730-23738
ISSN号	1520-6106
DOI	10.1021/jp0552877
文献子类	Article
英文摘要	The unbinding process of E2020 ((R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine) leaving from the long active site gorge of Torpedo californica acetylcholinesterase (TcAChE) was studied by using steered molecular dynamics (SMD) simulations on a nanosecond scale with different velocities, and unbinding force profiles were obtained. Different from the unbinding of other AChE inhibitors, such as Huperzine A that undergoes the greatest barrier located at the bottleneck of the gorge, the major resistance preventing E2020 from leaving the gorge is from the peripheral anionic site where E2020 interacts intensively with several aromatic residues (e.g., Tyr70, Tyr121, and Trp279) through its benzene ring and forms a strong direct hydrogen bond and a water bridge with Ser286 via its O24. These interactions cause the largest rupture force, similar to 550 pN. It was found that the rotatable bonds of the piperidine ring to the benzene ring and dimethoxyindanone facilitate E2020 to pass the bottleneck through continuous conformation change by rotating those bonds to avoid serious conflict with Tyr121 and Phe330. The aromatic residues lining the gorge wall are the major components contributing to hydrophobic interactions between E2020 and TcAChE. Remarkably, these aromatic residues, acting in three groups as "sender" and "receiver", compose a "conveyer belt" for E2020 entering and leaving the TcAChE gorge.
WOS关键词	ACTIVE-SITE GORGE ; TORPEDO-CALIFORNICA ; WATER-MOLECULES ; RAT-BRAIN ; PROTEIN ; LIGAND ; TACRINE ; CHOLINESTERASE ; HYPOTHESIS ; PROGRAM
WOS研究方向	Chemistry
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000233864300088
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273755]
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	Shen, JH
作者单位	1.Chinese Acad Sci, Ctr Drug Discovery & Design, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel 3.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China 4.Chinese Acad Sci, Grad Sch, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Niu, CY,Xu, YC,Xu, Y,et al. Dynamic mechanism of E2020 binding to acetylcholinesterase: A steered molecular dynamics simulation[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2005,109(49):23730-23738.
APA	Niu, CY.,Xu, YC.,Xu, Y.,Luo, XM.,Duan, WH.,...&Jiang, HL.(2005).Dynamic mechanism of E2020 binding to acetylcholinesterase: A steered molecular dynamics simulation.JOURNAL OF PHYSICAL CHEMISTRY B,109(49),23730-23738.
MLA	Niu, CY,et al."Dynamic mechanism of E2020 binding to acetylcholinesterase: A steered molecular dynamics simulation".JOURNAL OF PHYSICAL CHEMISTRY B 109.49(2005):23730-23738.