Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.

Despite the large number of studies available on nicotinic acetylcholine receptors, a complete account of the mechanistic aspects of their gating transition in response to ligand binding still remains elusive. As a first step toward dissecting the transition mechanism by accelerated sampling techniq...

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Autores principales:	Zeynab Mohammad Hosseini Naveh, Therese E Malliavin, Luca Maragliano, Grazia Cottone, Giovanni Ciccotti
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/44f37191074c46c2b4b5cd534581a205
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spelling	oai:doaj.org-article:44f37191074c46c2b4b5cd534581a2052021-11-18T08:32:38ZConformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.1932-620310.1371/journal.pone.0088555https://doaj.org/article/44f37191074c46c2b4b5cd534581a2052014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24551117/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Despite the large number of studies available on nicotinic acetylcholine receptors, a complete account of the mechanistic aspects of their gating transition in response to ligand binding still remains elusive. As a first step toward dissecting the transition mechanism by accelerated sampling techniques, we study the ligand-induced conformational changes of the acetylcholine binding protein (AChBP), a widely accepted model for the full receptor extracellular domain. Using unbiased Molecular Dynamics (MD) and Temperature Accelerated Molecular Dynamics (TAMD) simulations we investigate the AChBP transition between the apo and the agonist-bound state. In long standard MD simulations, both conformations of the native protein are stable, while the agonist-bound structure evolves toward the apo one if the orientation of few key sidechains in the orthosteric cavity is modified. Conversely, TAMD simulations initiated from the native conformations are able to produce the spontaneous transition. With respect to the modified conformations, TAMD accelerates the transition by at least a factor 10. The analysis of some specific residue-residue interactions points out that the transition mechanism is based on the disruption/formation of few key hydrogen bonds. Finally, while early events of ligand dissociation are observed already in standard MD, TAMD accelerates the ligand detachment and, at the highest TAMD effective temperature, it is able to produce a complete dissociation path in one AChBP subunit.Zeynab Mohammad Hosseini NavehTherese E MalliavinLuca MaraglianoGrazia CottoneGiovanni CiccottiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e88555 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zeynab Mohammad Hosseini Naveh Therese E Malliavin Luca Maragliano Grazia Cottone Giovanni Ciccotti Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.
description	Despite the large number of studies available on nicotinic acetylcholine receptors, a complete account of the mechanistic aspects of their gating transition in response to ligand binding still remains elusive. As a first step toward dissecting the transition mechanism by accelerated sampling techniques, we study the ligand-induced conformational changes of the acetylcholine binding protein (AChBP), a widely accepted model for the full receptor extracellular domain. Using unbiased Molecular Dynamics (MD) and Temperature Accelerated Molecular Dynamics (TAMD) simulations we investigate the AChBP transition between the apo and the agonist-bound state. In long standard MD simulations, both conformations of the native protein are stable, while the agonist-bound structure evolves toward the apo one if the orientation of few key sidechains in the orthosteric cavity is modified. Conversely, TAMD simulations initiated from the native conformations are able to produce the spontaneous transition. With respect to the modified conformations, TAMD accelerates the transition by at least a factor 10. The analysis of some specific residue-residue interactions points out that the transition mechanism is based on the disruption/formation of few key hydrogen bonds. Finally, while early events of ligand dissociation are observed already in standard MD, TAMD accelerates the ligand detachment and, at the highest TAMD effective temperature, it is able to produce a complete dissociation path in one AChBP subunit.
format	article
author	Zeynab Mohammad Hosseini Naveh Therese E Malliavin Luca Maragliano Grazia Cottone Giovanni Ciccotti
author_facet	Zeynab Mohammad Hosseini Naveh Therese E Malliavin Luca Maragliano Grazia Cottone Giovanni Ciccotti
author_sort	Zeynab Mohammad Hosseini Naveh
title	Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.
title_short	Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.
title_full	Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.
title_fullStr	Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.
title_full_unstemmed	Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.
title_sort	conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/44f37191074c46c2b4b5cd534581a205
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Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.

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