Vesicle protrusion induced by antimicrobial peptides suggests common carpet mechanism for short antimicrobial peptides

Abstract

Abstract Short cationic alpha-helical antimicrobial peptides (SCHAMPs) are promising candidates to combat the growing global threat of antimicrobial resistance. They are short-sequenced, selective against bacteria and have rapid action by destroying membranes. The full understanding of their mechanism of action will provide key information to design more potent and selective SCHAMPs. Molecular Dynamics (MD) simulations are invaluable tools that provide detailed insights of the peptide:membrane interaction at the atomic- and meso-scale level. Here we use atomistic and coarse-grained MD to investigate the detailed steps in the interaction of four promising SCHAMPs with membranes, namely BP100, Decoralin, Neurokinin-1, and Temporin L. Following experimental set-ups, we explored the effects of SCHAMPs on anionic membranes and vesicles at multiple peptide concentrations. Our results showed all four peptides shared similar binding steps, by binding initially to the membrane through electrostatic interactions and then flipping on their axis, dehydrating and inserting its hydrophobic moieties into the membrane core. At higher concentrations, fully alpha-helical peptides induced membrane budding and protrusions. Our results suggest the carpet mode of action is fit for the description of SCHAMPs lysis activity, and we discuss the importance of large hydrophobic residues in SCHAMPs design and activity.