Binding of Vitamin E in Model Membranes Studied by Umbrella Sampling Simulations

Abstract

Alpha tocopherol (αtoc), the form of vitamin E that is retained in the human body, is a lipid-soluble anti-oxidant. Its presumptive role is to protect polyunsaturated fatty acids (PUFA) from oxidation in cell membranes. The global concentration of αtoc in the plasma membrane is low (generally < 1 mol%), so preferential interaction with PUFA-containing phospholipids has been hypothesized to optimize protection of the lipid species most vulnerable to oxidative assault. To test this hypothesis we are investigating the desorption energy of αtoc in model membranes using umbrella sampling molecular dynamics (USMD) simulations. Insight into the flip-flop of αtoc across the membrane will also be obtained from the free energy barrier at the center of the bilayer. USMD simulations of αtoc molecules in membranes composed of 1-stearoyl-2-docosahexaenoylphosphatidylcholine (SDPC, 18:0-22:6PC) and, as a monounsaturated reference, 1-stearoyl-2-oleoylphosphatidylcholine (SOPC, 18:0-18:1PC) are now ongoing. The position of the chromanol group of αtoc in the membrane-normal direction is chosen to be the reaction coordinate. The simulations consist of 45 windows separated by 1 Å and arranged from the center of bilayer all the way to the bulk water, each sampled for 200 ns. Preliminary calculation of the mean force in SDPC shows that the equilibrium position for the chromanol group is around 12 Å from the bilayer center, consistent with our earlier simulations. More accurate calculation of the potential of mean force (PMF) is being performed using the weighted histogram analysis method (WHAM).