Characterizing the heterogeneity of membrane liquid-ordered domains

We use a lattice model of a ternary mixture containing saturated and unsaturated lipids with cholesterol (Chol), to study the structural properties characterizing the coexistence between the liquid-disordered and liquid-ordered phases. Depending on the affinity of the saturated and unsaturated lipids, the system may exhibit macroscopic (thermodynamic) liquid–liquid phase separation or be divided into small-size liquid-ordered domains surrounded by a liquid-disordered matrix. In both cases, it is found that the nanoscale structure of the liquid-ordered regions is heterogeneous, and that they are partitioned into Chol-rich sub-domains and Chol-free, gel-like, nano-clusters. This emerges as a characteristic feature of the liquid-ordered state, which helps distinguishing between liquid-ordered domains in a two-phase mixture, and similar-looking domains in a one-phase mixture that are rich in saturated lipids and Chol, but are merely thermal density fluctuations. The nano-structure heterogeneity of the liquid-ordered phase can be detected by suitable experimental spectroscopic methods and is observed also in atomistic computer simulations.