MULTISCALE MOLECULAR SIMULATIONS OF COMPLETE LOW-DENSITY LIPOPROTEIN PARTICLES

Low-density lipoprotein (LDL) is a large, heterogeneous lipid-protein assembly and the principal causal agent of atherosclerotic cardiovascular disease, the leading cause of death worldwide. LDL consists of a pseudo-structured lipid particle comprising a hydrophobic core of primarily cholesteryl esters and triglycerides encased by a phospholipid monolayer with free cholesterol distributed throughout. A single copy of apolipoprotein B-100 (apoB), one of the largest monomeric proteins in the human proteome, wraps around the particle to maintain its structural integrity and mediate clearance via the LDL receptor. Recently, we reported the first structure of full-length apoB [1], providing new insight into its domain organization and overall shape on the particle surface. However, critical structural details of the lipid particle itself remain poorly resolved, limiting our understanding of its active role in lipid metabolism. Multiscale molecular dynamics (MD) simulations offer a powerful complementary approach for resolving lipid organization and dynamics at high resolution. Here we present an integrative computational framework for constructing atomic and Martini coarse-grained models of complete LDL particles guided by cryo-electron microscopy data. Using multiscale MD simulations, we characterize particle morphology, lipid distribution and diffusion, and species-specific apoB-lipid interactions, providing a first, benchmark view of the internal lipid landscape of a complete LDL particle at molecular resolution. This work lays the groundwork for a systematic investigation of how lipid composition and organization contribute to LDL metabolic function and atherogenicity.