title: The enzymatic mechanism of carboxypeptidase: a molecular dynamics study.
abstract: An MD simulation of the system carboxypeptidase A (CPA) with the tetrapeptide Val-Leu-Phe-Phe has been performed in order to learn about the substrate disposition just prior to nucleophilic attack. We have explored the model in which the substrate does not substitute the zinc-coordinated water (the "water" mechanism). The simulations do suggest as feasible that the Zn-OH2 group performs a nucleophilic attack on the Phe-Phe peptidic bond. We have also investigated the model in which the carbonyl oxygen displaces the zinc-coordinated water. In this case the substrate and Glu-270 orient themselves to allow an anhydride intermediate during the peptidic bond cleavage (the "anhydride" mechanism). Based on the results of the simulations, both "water" and "anhydride" mechanisms are structurally feasible, although the former model seems more probable on chemical grounds.
authors.affiliation: Department of Chemistry, University of Florence, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Banci
authors.forename: I
authors.initials: I
authors.lastname: Bertini
authors.forename: G
authors.initials: G
authors.lastname: La Penna
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002268:Carboxypeptidases / Q000737:chemistry* / Q000378:metabolism; D043422:Carboxypeptidases A; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry; D011487:Protein Conformation; D013379:Substrate Specificity; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D009842:Oligopeptides; D014867:Water; D002268:Carboxypeptidases; D043422:Carboxypeptidases A