Cholesterol inhibits oxygen permeation through biological membranes: mechanism against double-bond peroxidation

The presence of oxygen molecules (O₂) in biological membranes promotes lipid peroxidation of phospholipids with unsaturated acyl chains. On the other hand, cholesterol is considered to be an antioxidant molecule as it has a significant barrier effect on the permeation of O₂ across membranes. However, a comprehensive explanation of how cholesterol affects the distribution and diffusion of O₂ within lipid bilayers is yet to be established. In this study, we investigated the interaction of oxygen molecules with polyunsaturated lipid bilayers using molecular dynamics (MD) simulations. The degree of lipid unsaturation and the concentration of cholesterol were varied to study the permeation of O₂. The free energy profile of O₂ diffusing from the water phase to the lipid bilayer was calculated using biased umbrella MD simulations. The results show that O₂ passively translocates into the membrane without changing the physical properties of the bilayer. Interestingly, in the unsaturated lipid bilayers the presence of cholesterol led to a significantly decreased permeation of O₂ and an increase in the lipid chain order. Our results indicate that the hydroxyl groups of cholesterol strongly interact with the O₂ molecules effectively inhibiting interactions between the oxygens and the double bonds in unsaturated lipid tails. In addition, a linear relationship between permeation and the ratio of membrane thickness and area per lipid was found. These insights can help our understanding of how the degree of unsaturation in a lipid tail and cholesterol affect lipid peroxidation at the molecular level.