Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.

α-Conotoxins potently inhibit isoforms of nicotinic acetylcholine receptors (nAChRs), which are essential for neuronal and neuromuscular transmission. They are also used as neurochemical tools to study nAChR physiology and are being evaluated as drug leads to treat various neuronal disorders. A numb...

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Autores principales:	Rilei Yu, David J Craik, Quentin Kaas
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e11921e0e7f943bbab70766ffe977b37
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spelling	oai:doaj.org-article:e11921e0e7f943bbab70766ffe977b372021-11-18T05:50:41ZBlockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.1553-734X1553-735810.1371/journal.pcbi.1002011https://doaj.org/article/e11921e0e7f943bbab70766ffe977b372011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21390272/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358α-Conotoxins potently inhibit isoforms of nicotinic acetylcholine receptors (nAChRs), which are essential for neuronal and neuromuscular transmission. They are also used as neurochemical tools to study nAChR physiology and are being evaluated as drug leads to treat various neuronal disorders. A number of experimental studies have been performed to investigate the structure-activity relationships of conotoxin/nAChR complexes. However, the structural determinants of their binding interactions are still ambiguous in the absence of experimental structures of conotoxin-receptor complexes. In this study, the binding modes of α-conotoxin ImI to the α7-nAChR, currently the best-studied system experimentally, were investigated using comparative modeling and molecular dynamics simulations. The structures of more than 30 single point mutants of either the conotoxin or the receptor were modeled and analyzed. The models were used to explain qualitatively the change of affinities measured experimentally, including some nAChR positions located outside the binding site. Mutational energies were calculated using different methods that combine a conformational refinement procedure (minimization with a distance dependent dielectric constant or explicit water, or molecular dynamics using five restraint strategies) and a binding energy function (MM-GB/SA or MM-PB/SA). The protocol using explicit water energy minimization and MM-GB/SA gave the best correlations with experimental binding affinities, with an R2 value of 0.74. The van der Waals and non-polar desolvation components were found to be the main driving force for binding of the conotoxin to the nAChR. The electrostatic component was responsible for the selectivity of the various ImI mutants. Overall, this study provides novel insights into the binding mechanism of α-conotoxins to nAChRs and the methodological developments reported here open avenues for computational scanning studies of a rapidly expanding range of wild-type and chemically modified α-conotoxins.Rilei YuDavid J CraikQuentin KaasPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 7, Iss 3, p e1002011 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Rilei Yu David J Craik Quentin Kaas Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.
description	α-Conotoxins potently inhibit isoforms of nicotinic acetylcholine receptors (nAChRs), which are essential for neuronal and neuromuscular transmission. They are also used as neurochemical tools to study nAChR physiology and are being evaluated as drug leads to treat various neuronal disorders. A number of experimental studies have been performed to investigate the structure-activity relationships of conotoxin/nAChR complexes. However, the structural determinants of their binding interactions are still ambiguous in the absence of experimental structures of conotoxin-receptor complexes. In this study, the binding modes of α-conotoxin ImI to the α7-nAChR, currently the best-studied system experimentally, were investigated using comparative modeling and molecular dynamics simulations. The structures of more than 30 single point mutants of either the conotoxin or the receptor were modeled and analyzed. The models were used to explain qualitatively the change of affinities measured experimentally, including some nAChR positions located outside the binding site. Mutational energies were calculated using different methods that combine a conformational refinement procedure (minimization with a distance dependent dielectric constant or explicit water, or molecular dynamics using five restraint strategies) and a binding energy function (MM-GB/SA or MM-PB/SA). The protocol using explicit water energy minimization and MM-GB/SA gave the best correlations with experimental binding affinities, with an R2 value of 0.74. The van der Waals and non-polar desolvation components were found to be the main driving force for binding of the conotoxin to the nAChR. The electrostatic component was responsible for the selectivity of the various ImI mutants. Overall, this study provides novel insights into the binding mechanism of α-conotoxins to nAChRs and the methodological developments reported here open avenues for computational scanning studies of a rapidly expanding range of wild-type and chemically modified α-conotoxins.
format	article
author	Rilei Yu David J Craik Quentin Kaas
author_facet	Rilei Yu David J Craik Quentin Kaas
author_sort	Rilei Yu
title	Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.
title_short	Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.
title_full	Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.
title_fullStr	Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.
title_full_unstemmed	Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.
title_sort	blockade of neuronal α7-nachr by α-conotoxin imi explained by computational scanning and energy calculations.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/e11921e0e7f943bbab70766ffe977b37
work_keys_str_mv	AT rileiyu blockadeofneuronala7nachrbyaconotoxinimiexplainedbycomputationalscanningandenergycalculations AT davidjcraik blockadeofneuronala7nachrbyaconotoxinimiexplainedbycomputationalscanningandenergycalculations AT quentinkaas blockadeofneuronala7nachrbyaconotoxinimiexplainedbycomputationalscanningandenergycalculations
_version_	1718424822680125440

Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.

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