Molecular Basis of Ligand Dissociation in β-Adrenergic Receptors 英文参考文献.docVIP

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Molecular Basis of Ligand Dissociation in β-Adrenergic Receptors 英文参考文献.doc

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Molecular Basis of Ligand Dissociation in β-Adrenergic Receptors 英文参考文献

MolecularBasisofLigandDissociationinb-Adrenergic Receptors AngelGonza′lez1,2,TomasPerez-Acle3,4,5,LeonardoPardo1,XavierDeupi6* 1LaboratorideMedicinaComputacional,UnitatdeBioestad?′stica,FacultatdeMedicina,UniversitatAuto`nomadeBarcelona,Bellaterra,Catalunya,Spain,2Departamento de Ciencias Biolo′gicas, Facultad de Ciencias Biolo′gicas, Universidad Andre′s Bello, Santiago, Chile, 3Computational Biology Lab, Center for Mathematical Modeling, FacultaddeCienciasF?′sicasyMatema′ticas,UniversidaddeChile,Santiago,Chile,4CentroInterdisciplinariodeNeurocienciasdeValpara?′so,PlayaAncha,Valpara?′so,Chile, 5Fundacio′nCienciaparalaVida,N?un?oa,Santiago,Chile,6CondensedMatterTheoryGroupandLaboratoryofBiomolecularResearch,PaulScherrerInstitut,VilligenPSI, Switzerland Abstract Theimportantanddiversebiologicalfunctionsofb-adrenergicreceptors(bARs)havepromotedthesearchforcompounds to stimulate or inhibit their activity. In this regard, unraveling the molecular basis of ligand binding/unbinding events is essential to understand the pharmacological properties of these G protein-coupled receptors. In this study, we use the steeredmoleculardynamicssimulationmethodtodescribe,inatomicdetail,theunbindingprocessoftwoinverseagonists, whichhavebeenrecentlyco-crystallizedwithb1andb2ARssubtypes,alongfourdifferentchannels.Ourresultsindicatethat this type of compounds likely accesses the orthosteric binding site of bARs from the extracellular water environment. Importantly,reconstructionofforcesandenergiesfromthesimulationsofthedissociationprocesssuggests,forthefirst time,thepresenceofsecondarybindingsiteslocatedintheextracellularloops2and3andtransmembranehelix7,where ligandsaretransientlyretainedbyelectrostaticandVanderWaalsinteractions.Comparisonoftheresiduesthatformthese new transient allosteric binding sites in both bARs subtypes reveals the importance of non-conserved electrostatic interactionsaswellasconservedaromaticcontactsintheearlystepsofthebindingprocess. Citation:Gonza′lezA,Perez-Acle