Molecular Dynamics Simulations of the Mononuclear Zinc-β-lactamase fromBacilluscereusComplexed with Benzylpenicillin and a Quantum Chemical Study of the Reaction Mechanism

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Abstract
Herein, we present results from MD simulations of the Michaelis complex formed between the B. cereus zinc-β-lactamase enzyme and benzylpenicillin. The structural and dynamical effects induced by substrate-binding, the specific role of the conserved residues, and the near attack conformers of the Michaelis complex are discussed. Quantum chemical methods (HF/6-31G* and B3LYP/6-31G*) are also applied to study the hydrolysis reaction of N-methylazetidinone catalyzed by a monozinc system consisting of the side chains of the histidine residues (His86, His88, and His149) complexed with Zn−OH and the side chains of Asp90 and His210. From this model system, we built molecular-mechanics representations of the prereactive complex and transition state configurations docked into the active site. Linear-scaling semiempirical calculations coupled with a continuum solvent model were then performed on these static models. We propose that the experimental rate data for the B. cereus enzyme is compatible with a one-step mechanism for the hydrolysis of β-lactam substrates in which His210 acts as a proton donor.