Dialectics of antimicrobial peptides II: Theoretical models of pore formation and membrane protection

Abstract: Amphipathic peptides are considered promising antibiotics because of 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. We studied this interaction for different peptide concentration: low, high, and low concentration followed by the addition of peptides in high concentration. Here we provide the theoretical description of the pore formation mechanisms. We predicted theoretically that two peptide molecules are enough to locally 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 supposed to work at low peptide concentrations. When applied in high concentration, the one-sided adsorption of peptides onto a closed membrane generates lateral pressure in the contacting lipid monolayer and lateral tension in the opposing monolayer. Our calculations predicted such asymmetric pressure/tension to greatly facilitate the formation of large metastable pores at any point of the membrane, regardless of the distance to the nearest peptide molecule. We therefore refer to this mechanism of pore formation as non-local. When the application of peptides in low concentration is followed by high concentration addition, multiple small metastable pores are predicted to form in the membrane in accordance with the local mechanism. This prevents the generation of a large difference in lateral pressure/tension, thus protecting the membrane from the formation of large pores. The results of the theoretical analysis agree with the experimental data of the companion paper.