MULTI-SCALE MOLECULAR SIMULATIONS OF HUMAN LOW-DENSITY LIPOPROTEIN

Low-density lipoprotein (LDL) plays a vital role in human health by transporting cholesterol and triglycerides to tissues throughout the body. However, its accumulation and oxidation in arterial walls can trigger atherosclerosis and cardiovascular disease, a leading cause of death globally. LDL particles are highly heterogeneous, with a hydrophobic core of cholesteryl esters, triglycerides, and free cholesterol encased in a phospholipid monolayer. A single copy of apolipoprotein B-100 (apoB-100) wraps around the particle to maintain its cohesion and mediate clearance via the LDL-receptor. Despite its immense biological and clinical significance, apoB-100 has defied high-resolution structural determination due to its massive size (4563 residues), flexibility, and complex lipid associations. Here, we report the first full-length structure of human apoB-100, addressing this decades-long challenge in lipoprotein biology. Using an integrative approach of single-particle cryo-electron microscopy, AlphaFold2, and molecular dynamics (MD)-based flexible refinement, we determine the structure of LDL at two distinct particle sizes, providing a detailed picture of the conformational changes undergone by apoB-100 as it adapts to varying lipid compositions. Building on these structures, we further developed a Martini-based coarse-grained (CG) self-assembly protocol to generate fully lipidated LDL particles. Subsequent multi-scale MD simulations highlight conformation-specific lipid binding sites as well as marked differences in lipid dynamics and localization, suggesting mechanisms for lipid transfer. Taken together, these results provide a computational framework for systematically investigating the effects of lipid oxidation and disease-associated apoB-100 mutations on LDL function and pathology.