α-Tocopherol and a Polyunsaturated Phospholipid Prefer Each Other’s Company in Mixed Membranes with Raft-Forming Sphingomyelin and Cholesterol: MD Simulations

α-Tocopherol (αtoc), the biologically active form of vitamin E, protects membrane lipids from oxidative damage. Previous hypotheses suggest that αtoc preferentially associates with polyunsaturated phospholipids to optimize protection of the lipid species most susceptible to oxidation, but this idea is challenged by recent work showing lower affinity for polyunsaturated than monounsaturated phospholipids. With coarse-grained and all-atom MD simulations, in this study we explore the lateral distribution of αtoc in bilayers composed of mixtures of N-palmitoyl sphingomyelin (PSM), cholesterol, and 1-palmitoyl-2-docosaheaxaenoylphosphatidylcholine (PDPC) that separate into ordered raft-like domains enriched in saturated PSM and cholesterol, surrounded by disordered nonraft regions enriched in polyunsaturated PDPC. Analyses assigning lipids to raft-like and nonraft environments reveal that αtoc is largely excluded from PSM-rich/cholesterol-rich raft-like domains and preferentially accumulates with PDPC in nonraft regions. We suggest that the high concentration of cholesterol in lipid rafts drives αtoc into nonraft regions, facilitating its role as an antioxidant.