Dialectics of Antimicrobial Peptides II: Theoretical Models of Pore Formation and Membrane Protection

Amphipathic peptides are considered promising antibiotics due to their ability to form pores in bacterial membranes. In two companion papers, we analyzed both experimentally and theoretically the mechanisms and consequences of the interaction of two types of amphipathic peptides (magainin and melittin) with lipid membranes. In the companion paper, we experimentally studied this interaction for different peptide concentrations: low or high concentration, and a combination of low concentration followed by the addition of peptides in high concentration. Here we provide the theoretical description of the pore formation mechanisms. In the present work, we theoretically predicted that two peptide molecules are sufficient to induce the formation of a small metastable pore that continuously connects two membrane leaflets and allows peptide and lipid translocation between the leaflets. This mechanism (referred to as local) is thought to operate at low peptide concentrations. At high concentrations, the one-sided adsorption of peptides onto a closed membrane generates a lateral pressure in the contacting lipid monolayer and a lateral tension in the opposing monolayer. Our calculations predicted that such asymmetric pressure/tension would greatly facilitate the formation of large metastable pores at any point on the membrane, regardless of the distance to the nearest peptide molecule. We therefore refer to this mechanism of pore formation as nonlocal. If the application of peptides at low concentration is followed by the addition of high concentration, multiple small metastable pores are predicted to form in the membrane according to the local mechanism. This prevents the generation of a large lateral pressure/tension difference and thus protects the membrane from the formation of large pores. The results of the theoretical analysis are in agreement with the experimental data of the companion paper [Volovik et al., <i>Langmuir</i> 2025].