The dependence of lipid asymmetry upon polar headgroup structure

The effect of lipid headgroup structure upon the stability of lipid asymmetry was investigated. Using methyl-β-cyclodextrin-induced lipid exchange, sphingomyelin (SM) was introduced into the outer leaflets of lipid vesicles composed of phosphatidylglycerol, phosphatidylserine (PS), phosphatidylinositol, or cardiolipin, in mixtures of all of these lipids with phosphatidylethanolamine (PE), and in a phosphatidylcholine/phosphatidic acid mixture. Efficient SM exchange (>85% of that expected for complete replacement of the outer leaflet) was obtained for every lipid composition studied. Vesicles containing PE mixed with anionic lipids showed nearly complete asymmetry which did not decay after 1 day of incubation. However, vesicles containing anionic lipids without PE generally only exhibited partial asymmetry, which further decayed after 1 day of incubation. Vesicles containing the anionic lipid PS were an exception, showing nearly complete and stable asymmetry. It is likely that the combination of multiple charged groups on PE and PS inhibit transverse diffusion of these lipids across membranes relative to those lipids that only have one anionic group. Possible explanations of this behavior are discusse.