Blockade of Neuronal α7-nAChR by α-Conotoxin ImI Explained by Computational Scanning and Energy Calculations 英文参考文献.docVIP

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Blockade of Neuronal α7-nAChR by α-Conotoxin ImI Explained by Computational Scanning and Energy Calculations 英文参考文献.doc

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Blockade of Neuronal α7-nAChR by α-Conotoxin ImI Explained by Computational Scanning and Energy Calculations 英文参考文献

BlockadeofNeuronala7-nAChRbya-ConotoxinImI ExplainedbyComputationalScanningandEnergy Calculations RileiYu,DavidJ.Craik,QuentinKaas* DivisionofChemistryandStructuralBiology,InstituteforMolecularBioscience,TheUniversityofQueensland,Brisbane,Queensland,Australia Abstract a-Conotoxinspotentlyinhibitisoformsofnicotinicacetylcholinereceptors(nAChRs),whichareessentialforneuronaland neuromusculartransmission.TheyarealsousedasneurochemicaltoolstostudynAChRphysiologyandarebeingevaluated asdrugleadstotreatvariousneuronaldisorders.Anumberofexperimentalstudieshavebeenperformedtoinvestigatethe structure-activity relationships of conotoxin/nAChR complexes. However, the structural determinants of their binding interactionsarestillambiguousintheabsenceofexperimentalstructuresofconotoxin-receptorcomplexes.Inthisstudy, the binding modes of a-conotoxin ImI to the a7-nAChR, currently the best-studied system experimentally, were investigatedusingcomparativemodelingandmoleculardynamicssimulations.Thestructuresofmorethan30singlepoint mutantsofeithertheconotoxinorthereceptorweremodeledandanalyzed.Themodelswereusedtoexplainqualitatively 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 adistance dependentdielectric constant or explicitwater, or molecular dynamics using five restraint strategies)andabindingenergyfunction(MM-GB/SAorMM-PB/SA).Theprotocolusingexplicitwaterenergyminimization andMM-GB/SAgavethebestcorrelationswithexperimentalbindingaffinities,withanR2valueof0.74.ThevanderWaals andnon-polardesolvationcomponentswerefoundtobethemaindrivingforceforbindingoftheconotoxintothenAChR. TheelectrostaticcomponentwasresponsiblefortheselectivityofthevariousImImutants.Overall,thisstudyprovidesnovel insightsintothebindingmechanismofa-conotoxinstonAChRsandthemethodologicaldevelopmentsreportedhereopen ave