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Binding of long-chain alpha-neurotoxin would stabilize the resting state of nAChR: a comparative study with alpha-conotoxin.

ABSTRACT: BACKGROUND: The details of interaction in a complex between potent antagonists such as long chain alpha-neurotoxins and alpha-conotoxins with nicotinic acetylcholine receptor (nAChR), and conformational changes induced by these antagonists, are not yet clear. MODELING: In order to uncover some of these critical structural features, we conducted a docking simulation and a molecular dynamics simulation (MD) of a model of the ligand binding domain of nAChR in complex with a long-chain alpha-neurotoxin and an alpha-conotoxin. RESULTS: Our docking results confirm the claim that T.nAChR is in the basal or resting state, which favors binding to the alpha-neurotoxins. Moreover, more correct "hits" for the alpha/gamma interface upon docking for conotoxin-nAChR confirm the preference of conotoxin GI for the alpha/gamma interface. More importantly, upon binding of alpha-neurotoxin, ligand-bonded nAChR is less dynamic in certain domains than the apo form of the conotoxin-AChR complex. Some critical interactions in the binding site such as the salt bridge formed between K145/D200 in the neurotoxin-nAChR complex is further stabilized during the MD simulation, while it is obviously more labile in the apo form. CONCLUSION: These observations could support the claim that alpha neurotoxins stabilize the nAChR resting state.

SUBMITTER: Nasiripourdori A

PROVIDER: S-EPMC2649906 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Binding of long-chain alpha-neurotoxin would stabilize the resting state of nAChR: a comparative study with alpha-conotoxin.

Nasiripourdori Adak A Ranjbar Bijan B Naderi-Manesh Hossein H

Theoretical biology & medical modelling 20090211

<h4>Background</h4>The details of interaction in a complex between potent antagonists such as long chain alpha-neurotoxins and alpha-conotoxins with nicotinic acetylcholine receptor (nAChR), and conformational changes induced by these antagonists, are not yet clear. MODELING: In order to uncover some of these critical structural features, we conducted a docking simulation and a molecular dynamics simulation (MD) of a model of the ligand binding domain of nAChR in complex with a long-chain alpha- ...[more]

PMID: 19210780

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Project description:?-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 ?-conotoxin ImI to the ?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 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 ?-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 ?-conotoxins.

Dataset Information

Binding of long-chain alpha-neurotoxin would stabilize the resting state of nAChR: a comparative study with alpha-conotoxin.

Publications

Binding of long-chain alpha-neurotoxin would stabilize the resting state of nAChR: a comparative study with alpha-conotoxin.

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