Influence of F Repeats and Terminal Residue Polarity on Peptide–VIM-2 Metallo-β-Lactamase Interactions

The global surge in antimicrobial resistance is a major public health concern, largely driven by the dissemination of beta-lactamases. Among them, VIM-2 metallo-beta-lactamase (MBL) poses a significant therapeutic challenge. In this study, we explore the role of phenylalanine and lysine residues, especially their repeat patterns, in modulating peptide binding affinity and structural interactions with VIM-2. Docking, molecular dynamics simulations, free energy decomposition analysis and residue analysis were conducted on gut metagenome-derived AMPs, PolyF and a control peptide (PolyR). Binding affinity with VIM-2 decreased with declining F content, yet PolyF alone showed unexpectedly low binding. However, PolyF exhibited most negative polar solvation energy in free energy decomposition analysis. This indicates that F repeats play a role in stabilizing a VIM-2-peptide complex in presence of a solvent. PolyF peptide lacks favorable electrostatic or dynamic interactions, likely due to the absence of K residues. Interestingly, loop1 and loop2 analysis of VIM-2 revealed that F repeats interfere with the loops that play a role in functioning of substrate binding at the active site. Additionally, F repeats were found to bind to residues lying adjacent to or nearby active site residues, which points towards the fact that F helps other residues like K to bind more stably with active site residues of VIM-2. Finally, analog designing and analysis reveals that a balance of aromatic (F) and positively charged (K) residues could enhance peptide binding with MBLs like VIM-2 when having hydrophobic on N-terminal and positively charged on C-terminal.