ABSTRACT:In biological membranes, alpha-tocopherols (α-toc; vitamin E) protect polyunsaturated lipids from free radicals. Although the interactions of α-toc with nonoxidized lipid bilayers have been studied, their on oxidized bilayers remain unknown. In this study, atomistic molecular dynamics (MD) simulations of oxidized lipid bilayers were performed with varying concentrations of α-toc. Bilayers with 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine (PLPC) lipids and its aldehyde derivatives at 1:1 ratio were studied. Our simulations show that oxidized lipids self-assemble into aggregates with a water pore rapidly developing across the lipid bilayer. The free energy of transporting an α-toc molecule in a lipid bilayer suggests that α-tocs can passively adsorb into the bilayer. When α-toc molecules were present at low concentrations in bilayers containing oxidized lipids, the formation of water pores was slowed down. At high α-toc concentrations, no pores were observed. Based on the simulations, we propose that the mechanism of how α-toc inhibits pore formation in bilayers with oxidized lipids is the following: α-tocs trap the polar groups of the oxidized lipids at the membrane-water interface resulting in a decreased probability for the oxidized lipids to reach contact with the two leaflets and initiate pore formation. This demonstrates that α-toc molecules not only protect the bilayer from oxidation but also help to stabilize the bilayer after lipid peroxidation occurs. These results will help in designing more efficient molecules to protect membranes from oxidative stress.Biological membranes serve as a partition between cells and their environment. Under oxidative stress, unsaturated lipids present in cell membranes may become exposed to attacks by free radicals, that is, oxidation. Oxidation transforms some of the membrane lipids to oxidized ones such as hydroperoxide and aldehyde lipids.
1,2It has also been suggested that internal, that is intra-leaflet, oxidation may be important in altering bilayer properties.
3Lipid peroxidation is an important mechanism of cell membrane damage. [4][5][6] Previous experiments and computer simulations 4,[7][8][9][10][11][12][13][14] have demonstrated how oxidized lipids disturb and deform bilayers. The polar chains in oxidized lipids are energetically unfavorable to stay in the bilayer's interior resulting in the reversal of the polar lipid chain to the bilayer interface. 4,11,15,16 This reversal causes major changes in bilayer properties such as increase of area per lipid, bilayer thinning, decrease of lipid tail order parameter, and increase in water permeability. 4,12,[15][16][17][18] Recently, we performed MD simulations of lipid bilayers with oxidized lipids at high concentrations. Two major oxidized lipid species including hydroperoxide and aldehyde were studied. The results showed that only aldehyde lipids were able to induce pore formation across a PLPC lipid bilayer and cause significant bilayer deformation.
13,15α-toc is well-known as an efficient antioxidant ...