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.

ELViM: Exploring Biomolecular Energy Landscapes through Multidimensional Visualization

“…In such instances, ELViM can still provide a useful representation of the configurational space for visualization, but calculation of free energies may necessitate a reweighting procedure. For detailed examples, refer to our previous works. , …”

“…Through an iterative process, the method seeks to project an ensemble of conformations into two optimal dimensions, facilitating an intuitive visual analysis of the energy landscape. ELViM has been successfully applied in the study of various biomolecular systems, including an RNA tetraloop, ordered proteins, ,− and intrinsically disordered peptides , and proteins . We begin by discussing the general aspects of the method, subsequently delving into its intricacies, such as the dissimilarity metric, code details, iteration steps, and auxiliary tools, which are available at GitHub ().…”

Understanding the Energy Landscape of Intrinsically Disordered Protein Ensembles

“…Previous studies with ELViM were carried out using strictly molecular dynamics trajectories, and they have proven useful in the investigation of molecular mechanisms, identifying transition-state ensembles, folding routes, and metastable states. The analyzed systems encompass ordered proteins, ,, knotted proteins, disordered peptides and proteins, ,, and an RNA tetraloop . In the present study, we have addressed IDP ensembles that were obtained by a variety of integrative experimental and computational methods.…”