Molecular Dynamics Simulations Reveal Leaflet Coupling in Compositionally Asymmetric Phase-Separated Lipid Membranes.

The eukaryotic plasma membrane has an asymmetric distribution of its component lipids. Rafts that result from liquid-liquid phase separation are a feature of its exoplasmic leaflet, but how these exoplasmic leaflet domains are coupled to the cytoplasmic leaflet is not understood. These rafts can be studied in model membranes of three-component mixtures that produce coexisting liquid ordered (Lo) and liquid disordered (Ld) domains. We conducted all-atom molecular dynamics simulations of compositionally asymmetric lipid bilayers that reflect a more realistic model of the plasma membrane. One leaflet contained phase-separated domains with phosphatidylcholine and cholesterol, representing the exoplasmic leaflet, whereas the other contained phosphatidylethanolamine, phosphatidylserine, and cholesterol, which are the predominant components of the cytoplasmic leaflet. Inspired by findings of domain alignment across the two leaflets in compositionally symmetric model membranes, we examined the coupling between the two leaflets to see how the single-phase cytoplasmic leaflet would respond to phase separation in the other leaflet and if information could be communicated across the membrane. We found the region of the single-phase leaflet apposing the Lo domain to be slightly more ordered and thicker than the region apposing the Ld domain. The region across from the Lo domain is somewhat enriched in cholesterol and significantly depleted of polyunsaturated lipids.