Computational And Experimental Studies Of Gold Nanoparticle Templated Hdl-Like Nanoparticles For Cholesterol Metabolism

High-density lipoprotein (HDL) is involved in the transport and metabolism of phospholipids, triglycerides, and cholesterol. Mimics of HDL are being explored as potential therapeutic agents for removing excess cholesterol from arterial plaques. Gold nanoparticles (AuNPs) functionalized with apolipoprotein A-I (apoA-I), and with the lipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate] (PDP PE) have been demonstrated to be acceptors of cellular cholesterol. However, detailed structural properties of this functionalized HDL AuNP are not well understood. We combined coarse-grained and all-atom MD simulations to simulate the self-assembly of lipids and cholesteryl ester on the AuNP/apoA-I construct to gain insights into its structural properties, and further make comparisons with experimental results. We find that lipids are oriented differently in regions with and without apoA-I. We also find that in this functionalized HDL AuNP, the distribution of cholesteryl ester maintains a reverse concentration gradient that is similar to the gradient found in native HDL. Incubating the HDL AuNP with cholesterol and lecithin:cholesterol acyltransferase (LCAT) demonstrate the HDL AuNP is able to efficiently activate LCAT and form esterified cholesterol from free cholesterol and phospholipid.