Mutations in passive residues modulate 3D-structure of NDM (New Delhi metallo-β-lactamase) protein that endue in drug resistance: a MD simulation approach.

The ability of antimicrobial resistance developed by bacteria enhanced the complexity of bacterial treatment leading a serious threat to human health. Production of β-lactamase by bacteria that inactivates β-lactam is a generic cause of resistance. One such β-lactamase enzyme is New Delhi Metallo-β-lactamase (NDM) which is recently reported to have clinically more importance and recognized as an antibiotic resistance marker. Mutations in active and passive residues of NDM protein play a fateful role in the substrate and inhibitor specificity. In this study, in silico point mutations of residues near the active site and flexible regions of protein were investigated. Hybrid modelling and molecular dynamics (MD) simulations were carried to build up the mutant models and monitored structural stability. Molecular docking results articulated that mutant proteins had lesser binding affinities with methicillin, oxacillin and doripenem drugs. Further, to scrutinize the structural alterations and rescore the binding energies per-residue basis, MD simulations of wildtype (WT) and mutant (MT) NDM proteins with methicillin, oxacillin and doripenem were performed. Our results demonstrated that mutations in N193A, S217A, G219A and T262A residues led to protein destabilization and amend their binding affinities with methicillin, oxacillin and doripenem. The present study exploited computational approaches which displayed differential binding of drugs with WT and MT NDM proteins that confer resistance to oxacillin and doripenem. The study features the significance of passive residues, thus provides a clue to accelerate the process of designing an ergastic antibiotic against NDM protein. Communicated by Ramaswamy H. Sarma.