Insights into the interactions and molecular dynamics of potent inhibitory peptides against BLEG-1 B3 metallo-β-lactamase through molecular dynamics simulations

Abstract

In light of the global antibiotic resistance related to metallo-β-lactamases (MBL), the design and characterizations of inhibitory peptides against a novel, evolutionary divergent B3 MBL, termed BLEG-1 had been initiated previously. Among all the designed peptides, two peptides namely “Peptide R” and “Peptide S” exhibited notable inhibition against BLEG-1 as inferred from their IC 50 values of below 1 µM. Although the binding of both peptides to BLEG-1 had been evidenced through isothermal titration calorimetry (ITC), the dynamics and molecular details of the peptide binding remained unknown. In this study, we investigated the molecular dynamics (MD) of BLEG-1–R and BLEG-1–S complexes using in silico methods. Our findings reveal that the overall structural stability and protein compactness of BLEG-1 is maintained as the peptides adjusted their conformation in the enzyme prior to final stabilization. The polar residues positioned in the C-terminal active site of BLEG-1 could be particularly critical for anchoring peptide R and S in the catalytic groove, in addition to the stabilizing effects by other dipolar, hydrophobic and π-π interactions. This study predicted the conformational flexibility and binding hotspots of dual peptides in BLEG-1, providing information that may be useful for peptide design and engineering toward BLEG-1 and its structural homologs.