ab initio md studies of hiv1 protease：hiv1蛋白酶的从头计算分子动力学研究.ppt

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1、AbinitioMDstudiesofHIV-1ProteaseCandidate:StefanoPianaAgostinettiSupervisor:PaoloCarloniOutlineBiochemistryoftheenzymeHIV-1protease(HIV-1PR)ResultsTheActivesiteconformationalflexibilityinthefreeenzymeNMRsignalcalculationsintheHIV-1PR/PepstatinadductInterplaybetweenglobalproteinmoti

2、onsandthereactionmechanismofHIV-1PRConclusionsTheHIV-1ProteaseActiveSiteFlapFlapFulcrumFulcrumCantileverCantileverHIV-PRisrequiredforviralmaturationImmaturenon-infectiveviralparticlesHIV-1PRInfectiveVirusesHIV-1PRcleavespolypeptidechainsPolypeptidechain(Substrate)FlapFlapActivesite

3、TheHIV-1ProteasecleavagesiteAsp25Asp25’Gly27Gly27’Thr26Thr26’TheAspDyadprotonationstateAsp25Asp25’Asp25Asp25’Asp25Asp25’Unstable0.0kcal/Mol2.0kcal/MolMinimalmodelingoftheAspdyadAddingtheThr26-Gly27H-bondThepeptidebonddipolemomentTheHIV-1PR/Pepstatincomplex13CNMRofasparticacidsHOOOO

4、-180ppm175ppmD0.15ppm13CNMRoftheAspdyadintheHIV-1PR/PepstatincomplexHOOOO-178ppm172ppmIsotopicsubstitutionAbinitiocalculationsofthe13CNMRchemicalshiftoftheAspdyad176ppmAbinitiocalculationsofthe13CNMRchemicalshiftoftheAspdyad179ppm175ppmResonancestabilization175ppm180ppmMBOratio:1.0

5、0MBOratio:1.68ModelsystemcalculationsResonancede/stabilizingcontributionsThereactionmechanismCMDsimulation-thesystemHIV-1PR/SubstratecomplexflexibilityHIV-1PR/SubstratecomplexflexibilityHIV-1PR/SubstratecomplexflexibilitySubstratedisplacementsModelcomplexestostudythereactionprofile

6、>50kcal/Mol20kcal/Mol50kcal/MolTransitionstates50kcal/MolSingleprotontransfer20kcal/MolConcerteddoubleprotontransferReactionIntermediateActivesiteFlapsCantileverCantileverFulcrumDrug-resistantmutants