Unravelling the influence of surface lipids on the structure, dynamics and interactome of high-density lipoproteins.

Surface lipids influence the biological activities of high-density lipoproteins (HDLs) but their species-specific effects on HDL structure, dynamics, and surface interactome has remained unclear. Building upon the five-lipid species HDL models developed and characterised in previous work, representative models of the major HDL subpopulations found in human plasma containing apolipoprotein A-I (apoA-I) have been studied using molecular dynamics simulation to describe their varying degrees of surface lipidome complexity. Specifically, two additional sets of representative HDL subpopulation particles were developed, one with sphingomyelin (SM) and the other with SM, phosphatidylethanolamine, phosphatidylinositol, and ceramide in quantities reflecting average levels characterised for HDL subpopulations derived from normolipidemic patients. These lipid species were assessed in terms of HDL size, morphology, dynamics, and overall interactome. The findings reveal that the presence of a representative SM fraction marginally enhanced HDL interfacial curvature and surface monolayer rigidity, manifesting in tighter phospholipid packing and slower surface lipid dynamics relative to SM-deficient HDL models. Furthermore, the presence of SM resulted in a reduction in the solvent exposure of core lipids and cholesterol molecules, whilst also enhancing apolipoprotein conformational flexibility and its overall twisting across the HDL surface. The hydrophobicity of apoA-I-bound lipid patches and the proportion of apoA-I hydrophobic surface area is enhanced by the overall lipidation of apoA-I irrespective of lipid composition. These findings offer new insights into how the surface lipid composition of different HDL subpopulations can significantly impact the overall interactome of HDL particles, potentially influencing subpopulation-specific biological functions like lipid scavenging and receptor interactions.