Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations

Abstract Acetylcholinesterase, with a deep, narrow active-site gorge, attracts enormous interest due to its particularly high catalytic efficiency and its inhibitors used for treatment of Alzheimer’s disease. To facilitate the massive pass-through of the substrate and inhibitors, “breathing” motions...

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Autores principales:	Shanmei Cheng, Wanling Song, Xiaojing Yuan, Yechun Xu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/55b6ae60257f4292aada539feb55adcd
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spelling	oai:doaj.org-article:55b6ae60257f4292aada539feb55adcd2021-12-02T16:07:01ZGorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations10.1038/s41598-017-03088-y2045-2322https://doaj.org/article/55b6ae60257f4292aada539feb55adcd2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03088-yhttps://doaj.org/toc/2045-2322Abstract Acetylcholinesterase, with a deep, narrow active-site gorge, attracts enormous interest due to its particularly high catalytic efficiency and its inhibitors used for treatment of Alzheimer’s disease. To facilitate the massive pass-through of the substrate and inhibitors, “breathing” motions to modulate the size of the gorge are an important prerequisite. However, the molecular mechanism that governs such motions is not well explored. Here, to systematically investigate intrinsic motions of the enzyme, we performed microsecond molecular dynamics simulations on the monomer and dimer of Torpedo californica acetylcholinesterase (TcAChE) as well as the complex of TcAChE bound with the drug E2020. It has been revealed that protein-ligand interactions and dimerization both keep the gorge in bulk, and opening events of the gorge increase dramatically compared to the monomer. Dynamics of three subdomains, S3, S4 and the Ω-loop, are tightly associated with variations of the gorge size while the dynamics can be changed by ligand binding or protein dimerization. Moreover, high correlations among these subdomains provide a basis for remote residues allosterically modulating the gorge motions. These observations are propitious to expand our understanding of protein structure and function as well as providing clues for performing structure-based drug design.Shanmei ChengWanling SongXiaojing YuanYechun XuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shanmei Cheng Wanling Song Xiaojing Yuan Yechun Xu Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations
description	Abstract Acetylcholinesterase, with a deep, narrow active-site gorge, attracts enormous interest due to its particularly high catalytic efficiency and its inhibitors used for treatment of Alzheimer’s disease. To facilitate the massive pass-through of the substrate and inhibitors, “breathing” motions to modulate the size of the gorge are an important prerequisite. However, the molecular mechanism that governs such motions is not well explored. Here, to systematically investigate intrinsic motions of the enzyme, we performed microsecond molecular dynamics simulations on the monomer and dimer of Torpedo californica acetylcholinesterase (TcAChE) as well as the complex of TcAChE bound with the drug E2020. It has been revealed that protein-ligand interactions and dimerization both keep the gorge in bulk, and opening events of the gorge increase dramatically compared to the monomer. Dynamics of three subdomains, S3, S4 and the Ω-loop, are tightly associated with variations of the gorge size while the dynamics can be changed by ligand binding or protein dimerization. Moreover, high correlations among these subdomains provide a basis for remote residues allosterically modulating the gorge motions. These observations are propitious to expand our understanding of protein structure and function as well as providing clues for performing structure-based drug design.
format	article
author	Shanmei Cheng Wanling Song Xiaojing Yuan Yechun Xu
author_facet	Shanmei Cheng Wanling Song Xiaojing Yuan Yechun Xu
author_sort	Shanmei Cheng
title	Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations
title_short	Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations
title_full	Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations
title_fullStr	Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations
title_full_unstemmed	Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations
title_sort	gorge motions of acetylcholinesterase revealed by microsecond molecular dynamics simulations
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/55b6ae60257f4292aada539feb55adcd
work_keys_str_mv	AT shanmeicheng gorgemotionsofacetylcholinesteraserevealedbymicrosecondmoleculardynamicssimulations AT wanlingsong gorgemotionsofacetylcholinesteraserevealedbymicrosecondmoleculardynamicssimulations AT xiaojingyuan gorgemotionsofacetylcholinesteraserevealedbymicrosecondmoleculardynamicssimulations AT yechunxu gorgemotionsofacetylcholinesteraserevealedbymicrosecondmoleculardynamicssimulations
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Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations

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