title: A quantum mechanics/molecular mechanics study of the reaction mechanism of the hepatitis C virus NS3 protease with the NS5A/5B substrate.
abstract: Combined quantum mechanics and molecular mechanics (QM/MM) calculations were carried out to characterize the reaction mechanism of the NS3 protease with its preferred substrate (NS5A/5B). The main purpose of this study was to locate the barrier states and intermediates along the distinguished coordinate path (DCP) involved in this process. These structures, and in particular the one corresponding to the first barrier state and intermediate (B1 and I1), could be a starting point for the synthesis of inhibitors of this protease, which could be used to treat hepatitis C. The two first steps of the reaction mechanism were studied, i.e., the acylation step and the breaking of the peptide bond. The first step takes place through a tetracoordinated intermediate, as suggested from previous works on other Serine proteases. The importance of the different amino acid residues was also considered (perturbation study where the MM charges of each residue were set to zero independently). The residues of the oxyanion hole were confirmed as the most important for the electrostatic stabilization of the tetracoordinate intermediate. Moreover, the role of other residues, e.g., Arg-155 and Asp-79, was also explained.
authors.affiliation: Departament de Química Física i Centre de Recerca en Química Teòrica, Universitat de Barcelona i Parc Científic de Barcelona, C/ Martí i Franquès 1, 08028 Barcelona, Spain. carolina.oliva.garcia@gmail.com
authors.forename: Carolina
authors.initials: C
authors.lastname: Oliva
authors.forename: Alejandro
authors.initials: A
authors.lastname: Rodríguez
authors.forename: Miguel
authors.initials: M
authors.lastname: González
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D000215:Acylation; D000998:Antiviral Agents / Q000494:pharmacology; D001665:Binding Sites; D002384:Catalysis; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D008956:Models, Chemical; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011480:Protease Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011789:Quantum Theory; D055672:Static Electricity; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase