title: Dynamic mechanism of E2020 binding to acetylcholinesterase: a steered molecular dynamics simulation.
abstract: 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, approximately 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.
authors.affiliation: Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School, Shanghai 201203, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Niu
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Wenhu
authors.initials: W
authors.lastname: Duan
authors.forename: Israel
authors.initials: I
authors.lastname: Silman
authors.forename: Joel L
authors.initials: JL
authors.lastname: Sussman
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D000077265:Donepezil; D057927:Hydrophobic and Hydrophilic Interactions; D007189:Indans / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011789:Quantum Theory; D013237:Stereoisomerism
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase