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The enzymatic mechanism of carboxypeptidase: A molecular dynamics study
Author(s) -
Banci Lucia,
Bertini Ivano,
La Penna Giovanni
Publication year - 1994
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.340180210
Subject(s) - tetrapeptide , nucleophile , chemistry , carboxypeptidase a , carboxypeptidase , stereochemistry , molecular dynamics , substrate (aquarium) , bond cleavage , mechanism (biology) , zinc , cleavage (geology) , peptide bond , combinatorial chemistry , enzyme , catalysis , peptide , computational chemistry , organic chemistry , biochemistry , materials science , biology , philosophy , epistemology , ecology , fracture (geology) , composite material
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‐OH 2 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. © 1994 John Wiley & Sons, Inc.