Atomistic Simulations of Phosphatidylcholines and Cholesteryl Esters in High-Density Lipoprotein-Sized Lipid Droplet and Trilayer: Clues to Cholesteryl Ester Transport and Storage

Abstract

Cholesteryl esters (CEs) are the water-insoluble transport and storage form of cholesterol. For both transport and storage, phospholipids and proteins embrace the CEs to form an amphipathic monolayer that surrounds the CEs. CEs are transported extracellularly in lipoproteins and are stored intracellularly as cytoplasmic lipid droplets. To clarify the molecular phenomena related to the above structures, we conducted atomistic molecular-dynamics simulations for a spherical, approximately high density lipoprotein sized lipid droplet comprised of palmitoyl-oleoyl-phosphatidylcholine (POPC) and cholesteryl oleate (CO) molecules. An additional simulation was conducted for a lamellar lipid trilayer consisting of the same lipid constituents. The density profiles showed that COs were located in the core of the spherical droplet. In trilayer simulations, CO molecules were also in the core and formed two denser strata. This is remarkable because the intra- and intermolecular behaviors of the COs were similar to previous findings from bulk COs in the fluid phase. In accordance with previous experimental studies, the solubility of COs in the POPC monolayers was found to be low. The orientation distribution of the sterol moiety with respect to the normal of the system was found to be broad, with mainly isotropic or slightly parallel orientations observed deep in the core of the lipid droplet or the trilayer, respectively. In both systems, the orientation of the sterol moiety changed to perpendicular with respect to the normal close to the phopsholipid monolayers. Of interest, within the POPC monolayers, the intramolecular conformation of the COs varied from the previously proposed horseshoe-like conformation to a more extended one. From a metabolic point of view, the observed solubilization of CEs into the phospholipid monolayers, and the conformation of CEs in the phospholipid monolayers are likely to be important regulatory factors of CE transport and hydrolysis.

Identification of a novel lipid binding motif in apolipoprotein B by the analysis of hydrophobic cluster domains

“…8), POPC acyl chains become more ordered in the trilayer. Similar simulations and analyses of trilayers made of POPC and cholesteryl esters showed an increase of 1% in the surface area and a solubility of 8 mol % of the esters, but no change in the ordering of lipids (47). …”

Atomistic MD simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP

“…The lipid parameters were a mixture of the united atom force fi eld GROMOS and Berger, Edholm, and Jahnig ( 23 ) parameters. POPC and ChOE force fi elds were derived from published reports (24)(25)(26). A force fi eld for TO was kindly provided by the research group of Ilpo Vattulainen from Tampere University of Technology, Finland.…”

Lipid Simulations: A Perspective on Lipids in Action

“…For example, the properties of the lipoprotein core have been studied both for cholesteryl esters and triglycerides (Heikelä et al 2006;Hall et al 2008). HDL discs have also been paid considerable attention (Shih et al 2005(Shih et al , 2008Catte et al 2006), and recent work on spheroidal HDL has been very illuminating (Catte et al 2008;Koivuniemi et al 2009). Especially, HDL simulations have been able to provide a great deal of insight into the atomistic structure of both the lipid droplet and the apolipoproteins ApoA-I surrounding the lipid part of HDL, and the important role of free cholesterol in stabilizing ApoA-I structure at the surface of HDL has become apparent.…”