Domain Formation in Model Membranes: Insight From MD Simulations

Numerous health benefits are associated with dietary consumption of docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (n-3 PUFA) abundant in fish oils. Incorporation into membrane phospholipids and regulation of the size of lipid rafts is a potential underlying mechanism. These ordered domains enriched in sphingolipid and cholesterol floating in a surrounding sea of disordered lipid are purported to serve as the platform for signaling proteins. In this work, we used coarse grained (CG) MD simulations to study lateral organization in bilayer membranes comprised of mixtures of DHA-containing 1-palmitoyl-2-docosahexaenoylphosphatidylcholine (PDPC) with raft-forming N-palmitoylsphingomyelin (PSM) and cholesterol. An analysis that applies a sliding window approach to assign lipids to raft-like PSM-rich/cholesterol-rich domains based on local lateral density was developed. Two projects are described.In the first project, we compared mixtures of PSM and cholesterol with polyunsaturated PDPC and/or monounsaturated 1-palmitoyl-2-oleoylphosphatidylcholine (POPC). Substituting PDPC for POPC was seen to promote the formation of larger raft-like PSM-rich/cholesterol-rich domains in simulations that were initially assembled as homogeneously mixed bilayers. The greater size was attributed to the larger difference in order between raft-like and non-raft environments due to disordering of the non-raft region produced by PDPC. This observation supports a role for DHA in controlling the size of lipid rafts and potentially the activation cell signaling proteins when rafts coalesce.In the second project, we studied where a-tocopherol (aToc) prefers to locate in simulations run on a bilayer composed of PSM, cholesterol and PDPC begun as a homogeneously mixed bilayer that then separated into PSM-rich/cholesterol-rich domains surrounded by a PDPC-rich environment. aToc, the biologically active form of the essential micronutrient vitamin E, is a membrane soluble antioxidant that prevents oxidative damage of lipids. The simulations reveal that almost all aToc resides in the disordered PDPC-rich environment, which we attributed to incompatibility with the high concentration of cholesterol or the associated high order in PSM-rich/cholesterol-rich domains. By co-localizing aToc with PDPC, protection of polyunsaturated phospholipids that are highly vulnerable to oxidation is optimized. Both projects demonstrate the utility of CG MD simulations that enable observation of the formation of nm-sized domains in membranes.