Quantum mechanical/molecular mechanical studies of zinc hydrolases

Metallo-enzymes play an indispensible role in many biological functions, and their modes of substrate binding and catalysis differ considerably from those of metal-free enzymes. A thorough understanding of the catalytic mechanisms of these enzymes cannot be achieved with experiments alone. In this review, recent theoretical investigations of the structure, binding, and catalysis of zinc hydrolases, which cleave substrate C-N and C-O bonds with high efficiency, are surveyed. Particular attention is paid to several extensively studied zinc peptidases as well as metallo--lactamases, which are responsible for ever-increasing bacterial resistance to penicillin-based antibiotics. These studies, particularly the ones using quantum mechanical/molecular mechanical methods, provide valuable insights into metal/ligand interactions, substrate binding and catalysis of these important metallo-enzymes.