A coarse-grained molecular dynamics study of nanoscale phospholipid-cholesterol vesicles: curvature effects on cholesterol distribution and vesicle structure.

Nanoscale lipid bilayer vesicles are widely used as model systems for exosomes and synaptic vesicles, released by cells for intercellular communication, in which strong membrane curvature couples molecular packing to asymmetry between the two lipid-bilayer monolayers. Here, we investigate DPPC, POPC or DLiPC phospholipid (PC)/cholesterol bilayer vesicles using coarse-grained molecular dynamics simulations, systematically varying phospholipid chain unsaturation, cholesterol content (0-50 mol%), and vesicle diameter (10-30 nm for the DPPC system). Cholesterol undergoes rapid redistribution on submicrosecond timescales, and is preferentially enriched in the inner leaflet of all vesicles studied, with the degree of asymmetry depending on the vesicle curvature, cholesterol content and PC chain saturation. Increasing cholesterol content induces bilayer thickening, reduced area per lipid and enhanced chain ordering. Highly curved vesicles are thinner than planar bilayers. These effects depend strongly on PC unsaturation and vesicle size, highlighting the synergistic role of these variables in controlling membrane structure and cholesterol partitioning in nanoscale vesicles.