STUDY OF ADSORPTION AND STRUCTURING OF L1A ANTIMICROBIAL PEPTIDE TO BACTERIAL MODEL MEMBRANE BY MOLECULAR DYNAMICS SIMULATIONS

The antibiotic resistance problem is a global concern, with expectations for the
development of new promising molecules to act against multi-resistant bacteria. The difficulty in using antimicrobial peptides (AMPs) as antibiotics lies in the
understanding of its mechanism of action. Although many papers highlight their in
vitro activity with promising results, it is necessary to understand their mechanism of action at a molecular level to avoid the development of antimicrobial resistance and enhance the activity of AMPs. The peptide L1A (sequence: IDGLKAIWKKVADLLKNT-NH2) was designed to have a higher net charge, a longer
amino acid sequence, and more distant acidic residues for better ion pairing
between amine groups compared to the Polybia Paulista antimicrobial peptide MP1
(sequence: IDWKKLLDAAKQIL-NH2), which showed broad-spectrum antimicrobial
activity, as well as promising results for anticancer action, with no cytotoxicity and
hemolysis in experiments with GUVs and LUVs. Experimental studies of L1A
suggested that the peptide has great selectivity for gram-negative bacteria and no
hemolysis, in addition to presenting a helical structure and amphipathic character,
which is crucial for its antimicrobial action. However, at the molecular level,details
regarding the mechanism of action of this peptide have not been fully clarified. The
present study aims to elucidate how the adsorption of peptide L1A occurs on anionic lipid bilayers containing phosphatidylcholine (PC) and phosphatidylglycerol (PG) (80:20 ratio), a model of bacterial membrane. To achieve this, Molecular Dynamics studies were performed with this system to understand the interactions involved in the adsorption and structuring of the peptide upon adsorption, providing new insights into its mechanism of action along with comparison with experimental results.