Asymmetry and heterogeneity in the plasma membrane

Plasma membranes (PMs) exhibit asymmetry between their two leaflets in terms of phospholipid headgroups, unsaturation, and resulting membrane properties, such as packing and fluidity. Lateral heterogeneity, including the formation of lipid domains, is another crucial aspect of PMs with significant biological implications. However, the nature and even the existence of lipid domains in the two leaflets of PMs remain elusive, hindering a complete understanding of the significance of lipid asymmetry. Using coarse-grained molecular dynamics simulations of the asymmetric PM, we find that the outer leaflet lipids are highly ordered and largely uniformly distributed, whereas the inner leaflet separates into nanoscale (≈10 nm) highly ordered and more disordered domains, exhibiting highly dynamic domain fusion and fission events. This structural asymmetry is further reinforced by asymmetric lateral stress resulting from a cholesterol bias toward the outer leaflet. These findings suggest distinct functional roles for the two leaflets modulated by asymmetric lateral stress. Additionally, comparing the phase behavior of asymmetric and fully scrambled PMs reveals a key determinant of domain size: intact PMs maintain nanoscale domains, whereas cell-derived giant PM vesicles, which have lost the strict lipid asymmetry, exhibit microscale domains.