Abstract

The interaction of amphipathic peptides with cellular membranes is a critical process in numerous biological phenomena, including host defense and drug delivery. This study investigates the mechanism of **pore formation by amphipathic peptides** in closed lipid bilayer membranes, a fundamental step in their lytic activity. Using a combination of fluorescence spectroscopy, dynamic light scattering, and molecular dynamics simulations, we examined the structural changes induced by the peptides in large unilamellar vesicles (LUVs) composed of various lipid mixtures. Our results demonstrate that the peptides initially partition into the lipid bilayer, followed by a concentration-dependent transition to a toroidal pore structure, characterized by a continuous lipid-peptide interface. The stability and size of these pores were found to be highly dependent on the peptide-to-lipid ratio and the membrane's intrinsic curvature stress. Specifically, anionic lipids were shown to enhance peptide binding and pore formation efficiency. These findings provide crucial insights into the biophysical principles governing peptide-mediated membrane disruption, which is essential for the rational design of novel antimicrobial agents and targeted drug delivery systems.