POSSIBLE BINDING ORIENTATIONS OF BETA-LACTAMS WITHIN STAPHYLOCOCCUS-AUREUS PC1 BETA-LACTAMASE SUGGEST FACTORS INVOLVED IN BETA-LACTAMASE RESISTANCE

The electrostatic forces within the active site of the beta-lactamase Staphylococcus aureus PC1 have been used to predict structures for the precatalytic complex with ampicillin, methicillin, clavulanate and im ipenem. There are significant differences in the orientation of these beta-lactams within the binding site, which explains the differences i n their resistance to the lactamase. The electrostatic forces were cal culated using a distributed multipole analysis of ab initio wave funct ions for both the lactams and the binding site residues, to ensure a g ood representation of the orientation dependence of this dominant cont ribution. The predicted binding orientations are contrasted with those predicted by overlaying the electrostatic extrema around the ligands. The accuracy of the ligand-only-based predictions is limited in some cases because of the subtle steric requirements of the lactamase bindi ng site.