AbinitioMDstudiesofHIV-1Protease：HIV-1蛋白酶的从头计算分子动力学研究

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

2、ybetweenglobalproteinmotionsandthereactionmechanismofHIV-1PRConclusionsTheHIV-1ProteaseActiveSiteFlapFlapFulcrumFulcrumCantileverCantileverHIV-PRisrequiredforviralmaturationImmaturenon-infectiveviralparticlesHIV-1PRInfectiveVirusesHIV-1PRcleavespolypeptidec

3、hainsPolypeptidechain(Substrate)FlapFlapActivesiteTheHIV-1ProteasecleavagesiteAsp25Asp25’Gly27Gly27’Thr26Thr26’TheAspDyadprotonationstateAsp25Asp25’Asp25Asp25’Asp25Asp25’Unstable0.0kcal/Mol2.0kcal/MolMinimalmodelingoftheAspdyadAddingtheThr26-Gly27H-bondThep

4、eptidebonddipolemomentTheHIV-1PR/Pepstatincomplex13CNMRofasparticacidsHOOOO-180ppm175ppmD0.15ppm13CNMRoftheAspdyadintheHIV-1PR/PepstatincomplexHOOOO-178ppm172ppmIsotopicsubstitutionAbinitiocalculationsofthe13CNMRchemicalshiftoftheAspdyad176ppmAbinitiocalcul

5、ationsofthe13CNMRchemicalshiftoftheAspdyad179ppm175ppmResonancestabilization175ppm180ppmMBOratio:1.00MBOratio:1.68ModelsystemcalculationsResonancede/stabilizingcontributionsThereactionmechanismCMDsimulation-thesystemHIV-1PR/SubstratecomplexflexibilityHIV-1P

6、R/SubstratecomplexflexibilityHIV-1PR/SubstratecomplexflexibilitySubstratedisplacementsModelcomplexestostudythereactionprofile>50kcal/Mol20kcal/Mol50kcal/MolTransitionstates50kcal/MolSingleprotontransfer20kcal/MolConcerteddoubleprotontransferReactionIntermed

7、iateActivesiteFlapsCantileverCantileverFulcrumDrug-resistantmutants