Ternary membranes composed of saturated phospholipids, unsaturated phospholipids, and cholesterol exhibit rich phase behavior shaped by mixing thermodynamics, giving rise to domains that are thought to play key roles in cellular behavior. Previous work has investigated how individual leaflet compositions respond to differential stress via cholesterol’s rapid flip-flop rate. It has also been well-demonstrated in both theory and simulation that lipids with different spontaneous curvatures can preferentially sort across leaflets according to the geometry of the bilayer. What is yet to be fully understood is the influence of spontaneous curvature on phase behavior and the magnitude of curvature-driven composition fluctuations. In this work, we are interested in long-timescale simulations where all phospholipids, not just cholesterol, are free to choose which leaflet they prefer. To practically run simulations that enable leaflet exchange, we implement nonequilibrium candidate Monte Carlo (NCMC) swap moves. We investigate both states inside and near the two-phase region, where large, long-lived composition fluctuations emerge. In strongly curved systems, we observe dramatic spontaneous symmetry breaking in leaflet composition, wherein one leaflet transiently enters two-phase coexistence while the other is correspondingly depleted. These results suggest that curvature is a consequential driver that can bias trajectories through composition space in mixtures with strong non-ideal interactions. By systematically varying membrane curvature and lipid spontaneous curvature (via bead-size tuning), we quantify the contribution of geometry to phase behavior. Together, our findings illustrate how curvature, fluctuations, and phase separation couple in multicomponent membranes, and they provide practical guidance for interpreting experiments on highly curved systems.
Zacharia et al. (Sun,) studied this question.