(267h) Lipid Phase Behavior of Low-Density Lipoprotein

Low-density lipoprotein is a core-shell lipid droplet that plays a key role in the onset of atherosclerosis, a leading cause of death. ApoB-100, one of the largest human proteins, stabilizes LDL by wrapping around the entire lipid droplet with a diameter of 21-27 nm. Historically, structural studies of LDL have been notoriously difficult. Recent cryo-electron microscopy (cryo-EM) studies reveal aspherical LDL and resolve most of apoB-100 and vague lipid structure. The regions of apoB-100 missing from the cryo-EM structure are related to flexible helical regions. The resolved lipid structure is attributed to amphiphilic lipids in the shell and core neutral lipids in a smectic phase. However, none of the lipids can be individually resolved. Overall, cryo-EM experiments reveal much about LDL, but there are lingering questions related to the aspherical shape of LDL, the missing regions of apoB-100, and the lipid structure. ­

Here, we use long timescale all-atom simulations of LDL to better understand the lipid structure and protein-lipid interactions that drive its aspherical shape. Specifically, the simulations of LDL are made up of a shell composed of apoB-100, phospholipids, and cholesterol, a core composed of cholesteryl esters and triglycerides, and solvent. We find there are significant interactions between the apoB-100 in the shell and the core lipids. Indeed, the core lipid phase is crucial to protein structure and overall LDL shape. Finally, we characterize the disease-related mutations of apoB-100 and known interaction sites with LDL receptors to draw new insights into the nature of lipid metabolic diseases.