The QM/MM barrier differences and similarity in free energy surfaces suggest that the activity difference between carbapenemases and carbapenem-inhibited enzymes arises from differences in the interactions of the carbapenem with its immediate environment. The active site of class A lactamases is reasonably well conserved between different family members, with shared structural motifs (Figure ). Aside from the catalytic residues Ser70 and Glu166, the active site components that are key for carbapenemase activity are the oxyanion hole (formed by the backbone amides of Ser70 and Ala/Ser/Thr237) and residues neighboring Glu166 and the deacylating water (Lys73, Asn132, Asn170) . In addition, interactions involving the 6-1R-hydroxyethyl group (that is part of the carbapenem core) may influence carbapenemase activity: it can form hydrogen bonds with active site residues as well as with the DW .In the following sections, we assess how these different factors affect the deacylation of the carbapenem acyl-enzyme complex.