COMPUTATIONAL INVESTIGATION OF MK PEPTIDE–MEMBRANE INTERACTIONS

Antimicrobial peptides interact with biological membranes through a combination of electrostatic attraction, hydrophobic interactions, and conformational adaptation, but the molecular determinants governing their membrane activity remain incompletely understood. Here, we investigate the molecular basis of the differential membrane interaction of three MK peptide analogs, MK4589, MK5789, and MK4578911, combining experimental data with atomistic molecular dynamics simulations. Experimental studies have shown distinct membrane-disruptive activities among these peptides, with MK4589 exhibiting the highest leakage activity and a pronounced transition toward an α-helical conformation upon interaction with anionic membranes.

To investigate the structural and energetic features underlying these differences, we performed all-atom molecular dynamics simulations for each peptide in both aqueous solution and a model lipid membrane. Three independent replicas were generated for each peptide in each environment, allowing the conformational behavior and peptide–membrane interactions to be sampled across multiple trajectories. The simulations were subsequently analyzed to characterize peptide conformational dynamics, membrane association, insertion, residue-specific interactions, hydrogen-bonding patterns, and the molecular organization of the peptide at the membrane interface. In addition, the simulation trajectories were subjected to Energy Landscape Visualization Method (ELViM) analysis to investigate the conformational landscapes and identify the major structural states sampled by each peptide.

This computational approach provides a molecular-level framework for connecting peptide sequence and structural properties with membrane interaction and disruption. By combining atomistic simulations with conformational landscape analysis and experimental observations, this study aims to elucidate the structural and energetic determinants governing the distinct membrane behaviors of MK peptide analogs.