Effects of Low-level Lipid Peroxidation on the Permeability of Nitroaromatic Molecules across a Membrane: A Computational Study

[Image: see text] Lipid peroxidation (LPO) in cellular membranes can cause severe membrane damage and potential cell death. Although oxidized phospholipids have been proved to lead to great changes in the structures and properties of membranes, effects of low-level LPO on membrane permeability have not yet been fully understood. Here, we explored the molecular mechanism of low-level LPO changing the permeability of nitroaromatic molecules across a lipid bilayer by all-atom molecular dynamics simulations. The results reveal that the enhanced passive transport of nitroaromatic molecules lies in the size of defects (i.e., water “finger” and “cone”), which is further dependent on the extent of LPO and the structural feature of solutes. In detail, if the solute can form more hydrogen bonds with water, which stabilizes the water into a large-size cone, there is a greater permeability coefficient (P). Otherwise, a small-size finger only results in a small increase of P. For example, the presence of 15% oxidized lipids could result in an increase of 2,4,6-trinitrotoluene (TNT’s) P by more than 2 orders of magnitude (from 1.7 × 10(–2) to 2.39 cm·s(–1)). The result suggests that the membrane permeability can be greatly promoted in the physiologically relevant environment with low-level LPO, and more importantly, clarifies the contributions of both the hydrophobicity of the membrane interior and the structural feature of solutes to such enhanced permeability. This work may provide significant insight into the toxic effects of nitroaromatic molecules and the pharmaceutical characteristics of tissues with oxidative damage.