Plasma membranes (PMs) exhibit both compositional and numerical asymmetry of phospholipids between their two leaflets. In addition, lateral heterogeneity, including the formation of lipid domains, is another key organizational feature of PMs with profound biological implications. However, the physical nature and even the existence of lipid domains in the two leaflets of PMs remain elusive, limiting our understanding of the functional significance of lipid asymmetry. In this study, we performed a coarse-grained molecular dynamics simulation of the asymmetric PM using the SPICA force field, based on recently reported lipidomic data of the mammalian red blood cell PM. Our simulation reveals that lipids in the outer leaflet are highly ordered and largely homogeneously distributed, whereas the inner leaflet separates into nanoscale coexisting ordered and disordered domains that undergo dynamic fusion and fission events. We further examined the effect of lipid scrambling—recently associated with extracellular vesicle formation and blebbing—on membrane bending rigidity. Our results show that a fully scrambled PM exhibits coexisting ordered and disordered domains in both leaflets and displays much larger undulations than the asymmetric PM, owing to domain anti-registration. Together, these findings suggest the functional meanings of lipid asymmetry and its transient loss. The broadly ordered outer leaflet restricts molecular permeation and thereby serves as a barrier to the extracellular environment. It also contributes to preserving membrane shape. In contrast, the dynamic domains in the inner leaflet regulate protein localization, which in turn facilitates signal transduction. Moreover, transient lipid scrambling induces pronounced undulations through domain anti-registration, consequently enabling membrane remodeling processes.
Yamada et al. (Sun,) studied this question.