Probing Mastoparan-like Antimicrobial Peptides Interaction with Model Membrane Through Energy Landscape Analysis

Abstract

Antimicrobial Peptides (AMPs) have emerged as promising alternatives to conventional antibiotics due to their capacity to disrupt the lipid packing of bacterial cell membranes. This mechanism of action may prevent the development of resistance by bacteria. Understanding their role in lipid packing disruption and their structural properties upon interaction with bacterial membranes is highly desirable. In this study, we employed Molecular Dynamics simulations and the Energy Landscape Visualization Method (ELViM) to characterize and compare the conformational ensembles of mastoparan-like Polybia-MP1 and its analogous H-MP1, in which histidines replace lysine residues. Two situations were analyzed: (i) the peptides in their free state in an aqueous solution containing water and ions and (ii) the peptides spontaneously adsorbing onto an anionic lipid bilayer, used as a bacteria membrane mimetic. ELViM was used to project a single effective conformational phase space for both peptides, providing a comparative analysis. This projection enabled us to map the conformational ensembles of each peptide in an aqueous solution and assess the structural effects of substituting lysines with histidines in H-MP1. Furthermore, a single conformational phase space analysis was employed to describe structural changes during the adsorption process using the same framework. We show that ELViM provides a comprehensive analysis, able to identify discrepancies in the conformational ensembles of these peptides that may affect their affinity to the membrane and adsorption kinetics.