Molecular dynamics characterization of the active cavity of carboxypeptidase A and some of its inhibitor adducts

Molecular dynamics (MD) calculations have been performed on carboxypeptidase A and on its adducts with inhibitors, such as d‐phenylalanine (dPhe) and acetate. The catalytically essential zinc ion present in the protein was explicitly included in all the simulations. The simulation was carried out over a sphere of 15 Å centered on the zinc ion. The crystallographic water molecules were explicitly taken into account; then the protein was solvated with a 18 Å sphere of water molecules. MD calculations were carried out for 45–60 ps. There is no large deviation from the available X‐ray structures of native and the dPhe adduct for the MD stuctures. Average MD structures were calculated starting from the X‐ray structure of the dPhe adduct, and, from a structure obtained by docking the inhibitor in the native structure. Comparison between these two structures and with that of the native protein shows that some of the key variations produced by inhibitor binding are reproduced by MD calculations. Addition of acetate induces structural changes relevant for the understanding of the interaction network in the active cavity. The structural variations induced by different inhibitors are examined. The effects of these interactions on the catalytic mechanism and on the binding of substrate are discussed. © 1992 Wiley‐Liss, Inc.