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

Yu, Rilei, Craik, David J. and Kaas, Quentin (2011) Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations. PLoS Computational Biology, 7 3: e1002011-1-e1002011-16. doi:10.1371/journal.pcbi.1002011


Author Yu, Rilei
Craik, David J.
Kaas, Quentin
Title Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations
Journal name PLoS Computational Biology   Check publisher's open access policy
ISSN 1553-734X
1553-7358
Publication date 2011-03-03
Year available 2011
Sub-type Article (original research)
DOI 10.1371/journal.pcbi.1002011
Open Access Status DOI
Volume 7
Issue 3
Start page e1002011-1
End page e1002011-16
Total pages 16
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Subject 1105 Ecology, Evolution, Behavior and Systematics
2611 Modelling and Simulation
2303 Ecology
1312 Molecular Biology
1311 Genetics
2804 Cellular and Molecular Neuroscience
1703 Computational Theory and Mathematics
Abstract alpha-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 a-conotoxin ImI to the alpha 7-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 R 2 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 alpha-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 aconotoxins.
Formatted abstract
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.
Keyword Biochemical Research Methods
Mathematical & Computational Biology
Biochemistry & Molecular Biology
Mathematical & Computational Biology
BIOCHEMICAL RESEARCH METHODS
MATHEMATICAL & COMPUTATIONAL BIOLOGY
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID ARC DP1093115
569539
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 20 Sep 2011, 22:43:56 EST by Dr Quentin Kaas on behalf of Institute for Molecular Bioscience