Exploring the Energetics of Membrane Fission Using Molecular Simulations

Membrane fission is a fundamental process underlying cellular trafficking, endocytosis, cytokinesis, and viral budding. The canonical fission pathway proceeds through two key steps: hemifission and rupture. Despite structural insights, the energetics of these intermediates remain experimentally elusive. Here, we establish a simulation framework to map the free-energy landscape of fission in cylindrical lipid bilayers using coarse-grained molecular dynamics simulations. By employing a collective variable (reaction coordinate), the potential of mean force is reconstructed to capture both the intact-to-hemifission and hemifission-to-rupture transitions. Our results reveal a complex influence of the tube radius on the fission energy barriers: while the hemifission barrier increases with tube radius due to enhanced membrane rigidity, the rupture barrier decreases as the curvature stress destabilizes the intermediate state. Lipid composition further modulates the pathway, with DOPE stabilizing the hemifission state more effectively than DOPC owing to its higher negative spontaneous curvature. Elevated membrane tension markedly lowers the hemifission barrier by lowering the inner tube radius and the lipid density. To demonstrate the broader applicability of our approach, we show that the influenza A M2 protein lowers the hemifission energy barrier, which is consistent with previous experimental observations. Together, these findings provide a mechanistic framework linking lipid mechanics, protein interactions, and external forces to the energetics of membrane fission.