Dynamic cholesterol redistribution favors membrane fusion pore constriction

Abstract

Previous experiments have shown that cholesterol strongly prefers concave leaflets (which have negative curvature and are typically thin), but cholesterol also orders and thickens bilayers (promoting liquid-ordered phases with positive curvature). Our all-atom molecular dynamics simulations resolve this discrepancy for highly curved fusion pores, similar to those found in the nascent fusion and terminal fission steps of endo-/exocytosis. We find that cholesterol is strongly excluded by bilayer thinning in the fusion pore neck, which is caused by the necks net negative Gaussian (saddle) curvature. Consistent with experiment and our fusion pore simulations, analysis of liquid-disordered planar bilayers indicates that cholesterol prefers overall thicker bilayers, but negative leaflet curvature. The exclusion of cholesterol from the neck because of saddle Gaussian curvature implies that it helps drive fusion pore closure, consistent with literature evidence that membrane reshaping is connected to lateral phase separation.