Does alpha-tocopherol flip-flop help to protect membranes against oxidation?
Alpha-tocopherols (-toc) are crucial in protecting biological membranes against oxidation by free radicals. We investigate the behavior of -toc molecules in lipid bilayers containing oxidized lipids by molecular dynamics (MD) simulations. To verify the approach, the location and orientation of -toc are first shown to be in agreement with previous experimental results. The simulations further show that -toc molecules stay inside the lipid bilayer with their hydroxyl groups in contact with the bilayer surface. Interestingly, interbilayer -toc flip-flop was observed in both oxidized and non-oxidized bilayers with significantly higher frequency in aldehyde lipid bilayer. Free energy calculations were performed and estimates of the flip-flop rates across the bilayers were determined. As the main finding, our results show that the presence of oxidized lipids leads to a significant decrease of free energy barriers and that the flip-flop rates depend on the type of oxidized lipid present. Our results suggest that -toc molecules could potentially act as high efficacy scavengers of free radicals to protect membranes from oxidative attack and help stabilize them under oxidative stress.