ATOMISTIC INSIGHTS FROM MOLECULAR DYNAMICS INTO THE PROTONATION-MODULATED INSERTION OF L1A AND L1Am PEPTIDES

Antimicrobial peptides (AMPs) are natural molecules with promising applications in medicine, agriculture, and the food industry. They typically act via electrostatic and hydrophobic interactions that lead to the adsorption and perturbation of bacterial membranes, increasing permeability and potentially causing lysis. L1A and L1Am are synthetic peptides derived from MP1, an AMP from the wasp Polybia paulista. Previous experimental work on L1A has shown deep membrane insertion and significant structural perturbations in bacterial model membranes. In this study, we use computer simulations to elucidate the molecular determinants governing the action of L1A and L1Am on lipid bilayers. We employed conventional molecular dynamics (MD) and constant-pH MD (CpHMD) to investigate the peptide adsorption process and the influence of protonation on peptide-membrane interactions and insertion. Our analysis reveals the dynamics of membrane insertion, its impact on lipid organization, and the crucial role of pH in modulating peptide charge and conformation. Furthermore, CpHMD simulations identify key residues that mediate these pH-dependent effects, advancing our understanding and informing the rational design of new antimicrobial agents.

This work was supported by Fundação para a Ciência e Tecnologia for projects UIDB/04046/2020 and UIDP/04046/2020. Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq #409272/2021-3, #404205/2024-0 and #200760/2025-4).