Possible binding orientations of β-lactams within Staphylococcus aureus PC1 β-lactamase suggest factors involved in β-lactamase resistance

Summary.

 The electrostatic forces within the active site of the β-lactamase Staphylococcus aureus PC1 have been used to predict structures for the precatalytic complex with ampicillin, methicillin, clavulanate and imipenem. There are significant differences in the orientation of these β-lactams within the binding site, which explains the differences in their resistance to the lactamase. The electrostatic forces were calculated using a distributed multipole analysis of ab initio wave functions for both the lactams and the binding site residues, to ensure a good representation of the orientation dependence of this dominant contribution. 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 binding site.