In my research, I used a highly detailed elastic model of lipid membranes to investigate how lipid demixing and membrane asymmetries drive budding at the nanoscale. To support this analytical approach, I performed coarse-grained molecular dynamics simulations to explore plausible parameters and guide intuition. The cover image of the June 3, 2025 issue of Biophysical Journal—a special issue on membrane fusion and budding—shows a Dry Martini simulation in which the outer leaflet contains a concentrated patch of lysophosphatidylcholine (lysoPC), a conical lipid that promotes positive curvature. The image captures a transient budding event driven purely by lipid composition and geometry, illustrating how asymmetry can cause complex membrane deformations.
This simulation was done early in the project to understand how strong lipid asymmetries affect membrane shape. A lysoPC-rich patch in the outer leaflet quickly triggered budding, but over time the bud retracted as lipids mixed—the neck widened, and the membrane flattened. The image shows this non-equilibrium state. Though not quantitative alone, the simulation helped narrow down plausible lipid concentrations and curvature ranges, guiding my theoretical parameter choices.
My findings reveal how nanoscale budding under physiological conditions depends on local lipid demixing and asymmetries in lipid composition, membrane area, and osmotic pressure. Smaller vesicles resist budding, but lipid demixing can significantly lower the energy barrier. Large compositional differences between bud and vesicle occur only when phase separation happens on the bud, highlighting the interplay between lipid organization and membrane shape. This process is vital for biological functions like endocytosis, viral budding, and intraluminal vesicle formation. In the latter case, intraluminal vesicles form by budding inward from the endosome membrane at the nanoscale, a process that involves membrane curvature and lipid asymmetry, making my findings directly relevant.
Thus, understanding the impact of asymmetry and lipid demixing on budding may enhance our comprehension of the regulation of these processes, their associated pathologies, and their sensitivity to membrane composition and geometry in general.
You can find more about my work on my personal blog and my Google Scholar profile.
—Itay Schachter