Blockade of Neuronal α7-nAChR by α-Conotoxin ImI Explained by Computational Scanning and Energy Calculations
Open Access
- 3 March 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Computational Biology
- Vol. 7 (3), e1002011
- https://doi.org/10.1371/journal.pcbi.1002011
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. Conotoxins are peptide toxins extracted from the venom of carnivorous marine cone snails. Members of the α-conotoxin subfamily potently block nicotinic acetylcholine receptors (nAChRs), which are involved in signal transmission between two neurons or between neurons and muscle fibers. nAChRs are important pharmacological targets due to their involvement in the transmission of pain stimuli and also in numerous neurone diseases and disorders. Their potency and specificity have led to the development of α-conotoxins as drug leads, and also to their use in the investigation of the role of nAChRs in various physiological processes. The most studied conotoxin/nAChR system, ImI/α7, was modeled in this study, and several computational methods were tested for their ability to explain the perturbations observed experimentally after introducing single point mutations into either ImI or the α7 receptor. The aim of this study was to establish a theoretical basis to rapidly identify new α-conotoxin mutants that might have improved specificity and affinity for a given receptor subtype. Furthermore, hundreds of thousands of conotoxins are predicted to exist, and computational methods are needed to help streamline the discovery of their molecular targets.Keywords
This publication has 63 references indexed in Scilit:
- Assessing the performance of the molecular mechanics/Poisson Boltzmann surface area and molecular mechanics/generalized Born surface area methods. II. The accuracy of ranking poses generated from dockingJournal of Computational Chemistry, 2010
- Gating of nicotinic ACh receptors: latest insights into ligand binding and functionJournal Of Physiology-London, 2010
- A Synthetic Combinatorial Strategy for Developing α-Conotoxin Analogs as Potent α7 Nicotinic Acetylcholine Receptor AntagonistsOnline Journal of Public Health Informatics, 2010
- MolProbity: all-atom structure validation for macromolecular crystallographyActa crystallographica. Section D, Structural biology, 2009
- Scanning Mutagenesis of α-Conotoxin Vc1.1 Reveals Residues Crucial for Activity at the α9α10 Nicotinic Acetylcholine ReceptorOnline Journal of Public Health Informatics, 2009
- Long-Range Coupling in an Allosteric Receptor Revealed by Mutant Cycle AnalysisBiophysical Journal, 2009
- Rational Design of α-Conotoxin Analogues Targeting α7 Nicotinic Acetylcholine ReceptorsOnline Journal of Public Health Informatics, 2009
- Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibitionProceedings of the National Academy of Sciences of the United States of America, 2008
- Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive functionBiochemical Pharmacology, 2007
- Comparative Protein Modelling by Satisfaction of Spatial RestraintsJournal of Molecular Biology, 1993