Additionally, the initial nucleophilic approach of the DW (from 3.5 Å to 2.2 Å) with the 6αhydroxyethyl moiety in orientation I and hydrogen bond configuration (1) is calculated to be slightly lower in energy for imipenem (Figure ). The DW remains hydrogen bonded to the hydroxyethyl oxygen during this approach, with the average distance to the hydroxyethyl methyl carbon reducing to about 3.3 Å. Notably, the initial approach between the DW and the carbapenem is also slightly higher in energy in orientations II and III than in orientation I, which may contribute to their overall energetics being less favorable for deacylation. However, the reasons for the preference for the imipenem, but not the meropenem, complex to adopt configuration (1) during deacylation are likely subtle and can result from small structural changes between the active site, substrate, and solvent molecules.