Domain stability in biomimetic membranes driven by lipid polyunsaturation

Biological membranes contain a broad variety of lipid species whose individual physicochemical properties and collective interactions ultimately determine membrane organization. A key aspect of the organization of cellular membranes is their lateral subdivision into domains of distinct structure and composition. The most widely studied membrane domains are lipid rafts, which are the biological manifestations of liquid-ordered phases that form in sterol-containing membranes. Detailed studies of biomimetic membrane mixtures have yielded wide-ranging insights into the physical principles behind lipid rafts; however, these simplified models do not fully capture the diversity and complexity of the mammalian lipidome, most notably in their exclusion of polyunsaturated lipids. Here, we assess the role of lipid acyl chain unsaturation as a driving force for phase separation using coarse-grained molecular dynamics (CGMD) simulations validated by model membrane experiments. The clear trends in our observations and good qualitative agreements between simulations and experiments support the conclusions that highly unsaturated lipids promote liquid-liquid domain stability by enhancing the differences in cholesterol content and lipid chain order between the coexisting domains. These observations reveal the important role of noncanonical biological lipids in the physical properties of membranes, showing that lipid polyunsaturation is a driving force for liquid-liquid phase separation.