Mechanism of Meropenem Hydrolysis by New Delhi Metallo β-Lactamase

New Delhi metallo β-lactamase (NDM-1) is a recent addition to the metallo-β-lactamases family that is capable of hydrolyzing most of the available antibiotics, including the new generation carbapenems. Here, we report the mechanism of Meropenem hydrolysis catalyzed by NDM-1 based on hybrid quantum-mechanical/molecular-mechanical metadynamics simulations. Our work elicits the molecular details of the catalytic mechanism and free energy profiles along the reaction pathway. We identified the ring opening step involving the nucleophilic addition of the bridging hydroxyl group on the β-lactam ring of the drug as the rate-determining step. Subsequent protonation of β-lactam nitrogen occurs from a bulk water molecule that diffuses into the active site and is preferred over proton transfer from the bridging hydroxyl group or from the protonated Asp124. The roles of important active site residues of NDM-1 and change in the coordination environment of Zn ions during the hydrolysis are also scrutinized.