Theoretical Models of Mechanisms of Membrane Activity of Linear Amphipathic Peptides

Abstract— Linear amphipathic peptides are components of some natural venoms exhibiting pronounced cytolytic activity. They are characterized by a low selectivity and a receptor-independent mechanism of action. Their common structural property is a spatial separation of hydrophobic and polar (charged) amino acid residues within a single molecule, as well as a relatively large positive electrical charge. Cytolytic peptides of venoms exhibit antimicrobial properties and are considered prototypes for potential antibiotics. Classical antimicrobial peptides have the same structural properties as the cytolytic peptides of natural venoms. Amphipathic peptides form pores in lipid membranes by two possible mechanisms: local and nonlocal. The local mechanism involves membrane destabilization immediately adjacent to the peptide molecule, partially embedded in the lipid monolayer. The nonlocal mechanism works only on closed membranes with one-sided addition of amphipathic peptides. In this case, the incorporation of peptides into the contact membrane monolayer induces lateral pressure in it and lateral tension in the opposite monolayer. This asymmetry in lateral tension/pressure facilitates the formation of large metastable lipid pores. In this study, we performed a theoretical analysis of the nonlocal mechanism of pore formation. Using the theory of lipid membrane elasticity, we calculated the dependences of pore energy on radius for various values of lateral tension and pressure in membrane monolayers and determined the dependences of the energy barriers to the formation and closure of a metastable pore, as well as of its radius, on lateral tension/pressure. A mechanism for the local formation of through defects in the membrane by single molecules of amphipathic peptides is proposed. Lipids and amphipathic peptides can pass through the defect walls to the opposite membrane monolayer. The structural characteristics of the peptides responsible for the efficient formation of defects are determined.