Simulations of Biased Agonists in the β2 Adrenergic Receptor with Accelerated Molecular Dynamics英文

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1、Articlepubs.acs.org/biochemistryTermsofUseSimulationsofBiasedAgonistsintheβ2AdrenergicReceptorwithAcceleratedMolecularDynamics,§§△#IrinaG.Tikhonova,*BalajiSelvam,AnthonyIvetac,JeffWereszczynski,△,▽,□,○andJ.AndrewMcCammon§MolecularTherapeutics,SchoolofPharmacy,MedicalBiologyCentre,Queen’sUni

2、versity,BelfastBT97BL,NorthernIreland,UnitedKingdom△DepartmentofChemistryandBiochemistry,UniversityofCaliforniaatSanDiego,LaJolla,California92093-0365,UnitedStates#DepartmentofPhysics,IllinoisInstituteofTechnology,Chicago,Illinois60616-3893,UnitedStates▽CenterforTheoreticalBiologicalPhysic

3、s,UniversityofCaliforniaatSanDiego,LaJolla,California92093-0365,UnitedStates□HowardHughesMedicalInstitute,UniversityofCaliforniaatSanDiego,LaJolla,California92093-0365,UnitedStates○DepartmentofPharmacology,UniversityofCaliforniaatSanDiego,LaJolla,California92093-0365,UnitedStates*SSupporti

4、ngInformationABSTRACT:ThebiasedagonismoftheGprotein-coupledreceptors(GPCRs),whereinadditiontoatraditionalGprotein-signalingpathwayaGPCRpromotesintracellularsignalsthoughβ-arrestin,isanovelparadigminpharmacology.BiochemicalandbiophysicalstudieshavesuggestedthataGPCRformsadistinctensembleofc

5、onformationssignalingthroughtheGproteinandβ-arrestin.Herewereportonthedynamicsoftheβ2adrenergicreceptorboundtotheβ-arrestinandGprotein-biasedagonistsandtheemptyreceptortofurthercharacterizethereceptorconformationalchangescausedbybiasedagonists.Weuseconventionalandacceleratedmoleculardynami

6、cs(aMD)simulationstoexploretheconformationaltransitionsoftheGPCRfromtheactivestatetotheinactivestate.WefoundthataMDsimulationsenablemonitoringofthetransitionwithinthenanosecondtimescalewhilecapturingtheknownmicroscopiccharacteristicsoftheinactivestates,suchastheioniclock,theinwardpositiono

7、fF6.44,andwaterclusters.Distinctconformationalstatesareshowntobestabilizedbyeachbiasedagonist.Inparticular,insimulationsofthereceptorwiththeβ-arrestin-biasedagonistN-cyclopentylbutanepherine,weobserveadifferentpatternofmotionsinhelix7whencomparedtosimulationswi