Ab initio MD studies of HIV-1 Protease,Candidate: Stefano Piana Agostinetti Supervisor: Paolo Carloni,Outline,Biochemistry of the enzyme HIV-1 protease (HIV-1 PR) Results The Active site conformational flexibility in the free enzyme NMR signal calculations in the HIV-1 PR/Pepstatin adduct Interplay between global protein motions and the reaction mechanism of HIV-1 PR Conclusions,The HIV-1 Protease,HIV-PR is required for viral maturation,Immature non-infective viral particles,Infective Viruses,HIV-1 PR cleaves polypeptide chains,Polypeptide chain (Substrate),Flap,Flap,Active site,The HIV-1 Protease cleavage site,The Asp Dyad protonation state,Unstable,0.0 kcal/Mol,2.0 kcal/Mol,Minimal modeling of the Asp dyad,Adding the Thr26-Gly27 H-bond,The peptide bond dipole moment,The HIV-1 PR/Pepstatin complex,13C NMR of aspartic acids,H,13C NMR of the Asp dyad in the HIV-1 PR/Pepstatin complex,178 ppm,172 ppm,Ab initio calculations of the 13C NMR chemical shift of the Asp dyad,Ab initio calculations of the 13C NMR chemical shift of the Asp dyad,Resonance stabilization,175 ppm,180 ppm,MBO ratio: 1.00,MBO ratio: 1.68,Model system calculations,Resonance de/stabilizing contributions,The reaction mechanism,CMD simulation - the system,HIV-1 PR/Substrate complex flexibility,HIV-1 PR/Substrate complex flexibility,HIV-1 PR/Substrate complex flexibility,Substrate displacements,Model complexes to study the reaction profile, 50 kcal/Mol,20 kcal/Mol,50 kcal/Mol,Transition states,Reaction Intermediate,Drug-resistant mutants,