Abstract

The plasma membrane of eukaryotic cells is characterized by a fundamental **lipid asymmetry**, where the outer and inner leaflets of the bilayer possess distinct lipid compositions. This asymmetry is crucial for numerous cellular processes, yet its role in the biophysical mechanism of **pore formation** remains incompletely understood. This study investigates the process of pore formation in model membranes exhibiting asymmetry in the lipid composition of their monolayers, a condition highly relevant to biological systems. Using a combination of theoretical modeling and molecular dynamics simulations, we explore how differential spontaneous curvature and surface tension between the two leaflets influence the energetic barrier and kinetics of pore creation. Our results demonstrate that lipid asymmetry significantly lowers the energy required for pore nucleation compared to symmetrical bilayers, primarily by promoting the formation of a **hydrophobic defect** at the bilayer midplane. Specifically, the leaflet with higher spontaneous curvature is shown to drive the initial destabilization. These findings provide critical insights into the physical principles governing membrane integrity and permeability, with implications for understanding processes such as electroporation, cell death, and the action of pore-forming toxins.