Conformational Changes in Acetylcholine Binding Protein Investigated by Temperature Accelerated Molecular Dynamicscottone

Abstract Despitethelargenumberofstudiesavailableonnicotinicacetylcholinereceptors,acompleteaccountof themechanistic aspectsof theirgatingtransitioninresponsetoligandbindingstill remainselusive.Asafirststeptowarddissectingthe transitionmechanismbyacceleratedsamplingtechniques,westudythe ligand-inducedconformational changesof the acetylcholinebindingprotein(AChBP),awidelyacceptedmodel forthefull receptorextracellulardomain.Usingunbiased MolecularDynamics(MD)andTemperatureAcceleratedMolecularDynamics(TAMD)simulationsweinvestigatetheAChBP transitionbetweentheapoandtheagonist-boundstate. InlongstandardMDsimulations,bothconformationsofthenative proteinarestable,whiletheagonist-boundstructureevolvestowardtheapooneiftheorientationoffewkeysidechainsin theorthostericcavityismodified.Conversely,TAMDsimulationsinitiatedfromthenativeconformationsareabletoproduce thespontaneoustransition.Withrespecttothemodifiedconformations,TAMDacceleratesthetransitionbyatleastafactor 10. Theanalysisof somespecific residue-residue interactionspointsout that thetransitionmechanismisbasedonthe disruption/formationof fewkeyhydrogenbonds.Finally,whileearlyeventsof liganddissociationareobservedalreadyin standardMD, TAMDaccelerates the liganddetachment and, at thehighest TAMDeffective temperature, it is able to produceacompletedissociationpathinoneAChBPsubunit.