Lipid demixing reduces energy barriers for high-curvature vesicle budding.

Under standard physiological conditions, budding relies on asymmetries, including differences in leaflet composition, area, and osmotic conditions, and involves large curvature changes in nanoscale lipid vesicles. So far, the combined impact of asymmetry and high curvatures on budding has remained unknown. Here, using the continuum elastic theory, the budding pathway is detailed under realistic conditions. The model enables a quantitative description of the budding process and the budded state of both ideally and nonideally mixed lipid nanoscale vesicles. It shows that budding is less favored in smaller vesicles but that lipid demixing can significantly reduce its energy barrier, and yet high compositional deviations of more than 7% between the bud and vesicle only occur with phase separation on the bud.