Structure-based computational study of the hydrolysis of New Delhi metallo-β-lactmase-1

New Delhi metallo-β-lactmase-1 (NDM-1) is an enzyme that confers antibiotic resistance to bacteria and is thus a serious threat to human health. Almost all clinically available β-lactam antibiotics can be hydrolyzed by NDM-1. To determine the mechanism behind the wide substrate diversity and strong catalytic ability of NDM-1, we explored the molecular interactions between NDM-1 and different β-lactam antibiotics using computational methods. Molecular dynamics simulations and binding free energy calculations were performed on enzyme-substrate (ES) complex models of NDM-1-Meropenem, NDM-1-Nitrocefin, and NDM-1-Ampicillin constructed by molecular docking. Our computational results suggest that mutant residues Ile35 and Lys216, and active site loop L1 residues 65–73 in NDM-1 play crucial roles in substrate recognition and binding. The results of our study provide new insights into the mechanism behind the enhanced substrate binding and wider substrate spectrum of NDM-1 compared with its homologous enzymes CcrA and IMP-1. These insights may be useful in the discovery and design of specific and potent inhibitors against NDM-1.

► Key residues in the interactions between NDM-1 and substrates have been identified.
► Two residues only present in NDM-1 are responsible for the enhance activity of NDM-1.
► Our studies suggest Loop L1 is important in substrate recognition and binding.