We have modelled carbapenem hydrolysis by the OXA-48 β-lactamase using QM/MM reaction simulations. The deacylation reaction was modelled for two carbapenem substrates, imipenem and meropenem, to deduce the origin of the higher activity towards imipenem compared to other carbapenems. MM MD simulations of the acylenzyme complexes demonstrate that the carbapenem tail (C2) groups are able to adopt many different conformations. In contrast, the carbapenem 6α-hydroxyethyl group is able to rotate and to adopt three specific different orientations, where it either interacts with the DW (I), Lys73 (III), or is rotated so that the methyl group is oriented towards Leu158 (II). Subsequently, deacylation was modelled using QM/MM for both substrates in these three orientations to investigate the effect of orientation upon deacylation efficiency. Our calculated free energy barriers indicate that the most deacylation-competent orientation is I, where the hydroxyl group interacts with the DW, and that the orientation III has the highest free energy barriers.