“Head-to-Toe” Lipid Properties Govern the Binding and Cargo Transfer of High-Density Lipoprotein

The viscoelastic properties of biological membranes are crucial in controlling cellular functions and are determined primarily by the lipids’ composition and structure. This work studies these properties by varying the structure of the constituting lipids in order to influence their interaction with high-density lipoprotein (HDL) particles. Various fluorescence-based techniques were applied to study lipid domains, membrane order, and the overall lateral as well as the molecule–internal glycerol region mobility in HDL–membrane interactions (i.e., binding and/or cargo transfer). The analysis of interactions with HDL particles and various lipid phases revealed that both fully fluid and some gel-phase lipids preferentially interact with HDL particles, although differences were observed in protein binding and cargo exchange. Both interactions were reduced with ordered lipid mixtures containing cholesterol. To investigate the mechanism, membranes were prepared from single-lipid components, enabling step-by-step modification of the lipid building blocks. On a biophysical level, the different mixtures displayed varying stiffness, fluidity, and hydrogen bond network changes. Increased glycerol mobility and a strengthened hydrogen bond network enhanced anchoring interactions, while fluid membranes with a reduced water network facilitated cargo transfer. In summary, the influence of chain length and the degree of saturation of the fatty acid chains, as well as the cholesterol content in the membrane, could be discerned. Major factors for increased interaction between lipid membranes and HDL particles are properties such as glycerol region mobility. By increasing the accessible surface area in the glycerol region, interaction occurs preferentially. However, the data indicate that neither the hydrogen bond network nor the glycerol region mobility alone are sufficient to fully explain the interaction with HDL particles.