Abstract

The antimicrobial activity of amphipathic peptides (AMPs) is fundamentally linked to their capacity to induce the formation of transmembrane pores in bacterial lipid membranes. While the general mechanism of pore formation is well-established, the precise molecular stoichiometry required for the initial pore-forming event remains a critical, unresolved question. This theoretical study investigates the energetic feasibility of pore formation in a planar lipid bilayer mediated by a small number of AMP molecules, specifically focusing on the scenario where two or more peptides line the pore's equator. Using a continuum elastic model, we calculated the energy of the pore edge and the energy of membrane deformations induced by the peptides in the planar bilayer. Our analysis demonstrates that for a narrow range of specific physicochemical and geometric characteristics of the AMP molecule, the energy associated with a pore lined by two or more peptides can be lower than the deformation energy induced by the same number of peptides in an intact bilayer. This finding suggests that a minimal assembly of just two AMP molecules is, in principle, sufficient to nucleate a stable, through-membrane pore. This insight into the minimum required peptide assembly provides a crucial constraint for developing more accurate kinetic models of AMP-mediated membrane lysis and informs the rational design of next-generation antimicrobial agents.