Molecular modelling studies on Henry-Michaelis complexes of a class-C beta-lactamase and beta-lactam compounds

Abstract

[eng] Molecular mechanics calculations based on the AMBER force field were used to construct molecular models for the Henry<br>Michaelis complexes of Enterobacter cloacae P99, a class C beta-lactamase, with various beta-lactam antibiotics. The results confirm the high significance of the carboxyl group borne by the beta-lactam to the binding interaction with the enzyme's active site. The differential conformation adopted by the carboxyl group in penicillins and cephalosporins clearly reflects in the behaviour of the complexes formed. Thus, penicillins and cephalosporins form a strong hydrogen bond between one of the oxygen atoms in the carboxyl group and the hydroxyl group in the side chain of Thr-316 and Ser-318, respectively. This differential interaction of the carboxyl group in the two types of antibiotic results in also differential interactions of the oxygen atom in the beta-lactam carbonyl with the Ser-64 and Ser-318 enzyme residues