COMPUTATIONAL ANALYSIS OF MASTOPARAN ANALOG PEPTIDES: INSIGHTS INTO ANTIBIOTIC ACTIVITY AND CONFORMATIONAL LANDSCAPE

Antimicrobial Peptides (AMPs) have emerged as promising alternatives to conventional antibiotics due to their capacity to disrupt the lipid packing of bacterial cell membranes and hinder the development of bacterial resistance. Understanding their role in lipid packing disruption and their structural properties upon interacting with bacterial membranes are crucial. Computational methods can provide valuable insights into the mechanism of action of AMPs and describe at an atomistic level the structural changes that occur when they adsorb onto an anionic lipid bilayer, their buried positioning, and the prevalence of interactions. In this study, a series of mastoparan analogs were analyzed. They were engineered based on strategies of Ala and Lys scanning concerning the sequences of classical mastoparans. Experimental data showed that the antibiotic activity of mastoparan analogs was directly dependent on the apparent extension of their hydrophilic surface, their molecules required four to six Lys residues in specific positioning of the peptide chain to achieve activities comparable to or higher than the reference antibiotic compounds, although their structure ensembles were not explored. The structural analysis in comparison with its activity could provide insights into other modifications to optimize AMPs. To perform this analysis, we employed Molecular Dynamics (MD) simulations and the Energy Landscape Visualization Method (ELViM) to characterize and compare the conformational ensembles of mastoparan analogous peptides generated from their spontaneous adsorption into anionic lipid bilayers bacterial mimetic. ELViM projects peptides structural ensembles into a single-effective conformational landscape, enabling a comparative analysis. This single-space framework allows for the comparison of conformational preferences among the analogs and enables the description of structural changes during the adsorption process. Discrepancies in the conformational ensembles of these peptides were compared with experimental activity studies to infer how different conformations and the activity are related.