Mechanism of Meropenem Hydrolysis by New Delhi Metallo
β‑Lactamase
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Abstract
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 Asp<sub>124</sub>. 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