Stability and fusion of lipid vesicles containing headgroup-modified analogues of phosphatidylethanolamine.

We have used lipid mixing, contents mixing and contents-leakage assays to characterize the divalent cation-mediated interactions of vesicles composed of various headgroup-modified analogues of phosphatidylethanolamine, PE (N- and C-2-alkylated derivatives, and analogues with increased separations of the phosphoryl and amino groups) together with a low mole percentage of phosphatidylserine (PS). Vesicles containing different structural analogues of PE exhibit marked differences, both in the threshold divalent cation concentrations that are required to initiate vesicle-vesicle interactions and in the rates of contents mixing and leakage observed at suprathresholds divalent cation concentrations. The efficiencies of divalent cation-promoted contents leakage, and to a slightly lesser extent those of contents mixing, for PS/PE (analogue) vesicles show a marked inverse correlation with the lamellar-to-hexagonal II transition temperature (TH) of the PE (analogue) component. However, the destabilization kinetics for such vesicles show no abrupt changes over the temperature range around the equilibrium TH value measured for the vesicle lipids. Vesicles combining PS with different PE analogues exhibit divalent cation thresholds for aggregation that are not correlated with the TH values of the PE (analogue) components but appear instead to be correlated with the equilibrium interbilayer separations measured in multilamellar dispersions of these species. We have identified headgroup-modified analogues of PE that can be used to prepare vesicles that fuse more rapidly under a given set of conditions, or that show a bette ratio of fusion-to-contents-leakage rates, than do PE-containing vesicles. These results may be useful both for understanding better the bases for the high fusion-supporting ability of PE and for the preparation of lipid vesicles 'tailored' for particular practical applications.