Long chain sphingomyelin depletes cholesterol from the cytoplasmic leaflet in asymmetric lipid membranes.

The transbilayer distribution of cholesterol (CHL) in complex asymmetric lipid membranes remains controversial, with contrasting investigations suggesting that there is more CHL either in the exoplasmic, outer leaflet (OL) or the cytoplasmic, inner leaflet (IL) depending on cell type or model, membrane composition, and method of investigation. Here, we launch systematic coarse-grained molecular dynamics simulations to investigate the impact of the sphingomyelin (SM) acyl chain length upon CHL distribution in asymmetric lipid membrane mixtures which account for the variation of the most abundant headgroups and acyl chain unsaturation in the two membrane leaflets. We find that there is always more CHL in the OL, but longer chain SM depletes more CHL from the IL than short chain SM in simple membrane mixtures containing SM and 16 : 0, 18 : 1 phospholipids.