Yang Hong, Zhou Mi, Li Huarong, Wei Tong, Tang Can, Zhou Yang, Long Xinping
School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China.
Institute of Chemical Materials, China Academy of Engineering and Physics, Mianyang 621900, China.
ACS Omega. 2020 Mar 6;5(10):4798-4806. doi: 10.1021/acsomega.9b03462. eCollection 2020 Mar 17.
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 (). Otherwise, a small-size finger only results in a small increase of . For example, the presence of 15% oxidized lipids could result in an increase of 2,4,6-trinitrotoluene (TNT's) by more than 2 orders of magnitude (from 1.7 × 10 to 2.39 cm·s). 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.
细胞膜中的脂质过氧化（LPO）可导致严重的膜损伤和潜在的细胞死亡。尽管氧化磷脂已被证明会导致膜的结构和性质发生巨大变化，但低水平LPO对膜通透性的影响尚未完全了解。在此，我们通过全原子分子动力学模拟探索了低水平LPO改变硝基芳香族分子跨脂质双层通透性的分子机制。结果表明，硝基芳香族分子被动运输的增强取决于缺陷的大小（即水“指状物”和“锥体”），这进一步取决于LPO的程度和溶质的结构特征。具体而言，如果溶质能与水形成更多氢键，使水稳定成大尺寸的锥体，则通透性系数（）更大。否则，小尺寸的指状物只会导致的小幅增加。例如，存在15%的氧化脂质可使2,4,6-三硝基甲苯（TNT）的增加超过2个数量级（从1.7×10到2.39 cm·s）。结果表明，在低水平LPO的生理相关环境中，膜通透性可大大提高，更重要的是，阐明了膜内部疏水性和溶质结构特征对这种增强通透性的贡献。这项工作可能为硝基芳香族分子的毒性作用和氧化损伤组织的药物特性提供重要见解。
