Conformation and Hydrodynamics of Spherical High-Density Lipoprotein and Its Specific Adsorption onto Different Membrane Surfaces

Abstract Spherical high-density lipoproteins (LpA-I HDL), consisting of apolipoprotein A-I (apoA-I), 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), cholesterol, triglyceride, and cholesteryl ester, adsorbed onto various lipid bilayers are simulated using all-atom models. First, LpA-I particles with different molar ratios are equilibrated in water, during which three apoA-I molecules adsorb onto the lipid particle by twisting their helical domains, consistent with the experimentally proposed trefoil model, which is further supported by hydrodynamic sizes and shapes, lysine cross-links, helicities, and component distributions of LpA-I particles. Intermolecular and intramolecular cross-links are distinguished, with specific lysine pairs remaining closely associated and contributing to the maintenance of the trefoil model. In particular, higher POPC content promotes the formation of many more hydrogen bonds with apoA-I, weakening intermolecular hydrogen bonds between apoA-I proteins and thus reducing apoA-I helicity. Binding free-energy calculations from umbrella sampling show strong adsorption of LpA-I onto bilayers composed of anionic lipids or zwitterionic lipids with relatively small amine headgroups, consistent with experiments. This adsorption is attributed to hydrogen-bonding interactions mediated by electrostatic forces between bilayer headgroups and apoA-I, especially within its C-terminal region, which also modulate the helicity of amphipathic apoA-I. These findings help explain experimental observations and proposed models regarding the conformation and hydrodynamics of spherical LpA-I HDL particles, as well as their protein corona formation on specific liposomes.