Peroxidation of plasma membranes, characterized by oxidative attack of lipidic carbon–carbon double-bonds in unsaturated fatty acids, has been identified as an important biochemical event in multiple pathological conditions, including neurodegenerative diseases, atherosclerosis, diabetes, preeclampsia, aging, cancer, etc. Changes to the lipid bilayer structure as a result of lipid peroxidation may lead to lipid membrane malfunction, and consequently initiate further downstream biochemical cascades. However, how lipid peroxidation modulates the mechanical properties of lipid membranes remains largely controversial. In this study, we investigate the peroxidation of lipids with polyunsaturated fatty acid tails using molecular dynamics simulations. By systematically varying the oxidation site, we find that lipid peroxidation alters the biophysical properties of bilayer membrane in a peroxidation site-specific manner. Specifically, our results suggest that peroxidation at sites in the bilayer interior disturbs and softens the membrane, whereas peroxidation at sites near the membrane–water interface results in a more ordered and stiffer membrane. Such a peroxidation site-specific modulation of lipid membrane mechanics provides an explanation for the contradictory results obtained in previous experiments. Our study paves the way for an improved understanding of the initiation of the downstream cellular dysfunction caused by lipid peroxidation.

质膜过氧化，以不饱和脂肪酸中脂碳-碳双键的氧化攻击为特征，已被确定为多种病理状况的重要生化事件，包括神经退行性疾病、动脉粥样硬化、糖尿病、先兆子痫、衰老、癌症等. 脂质过氧化导致脂质双层结构的变化可能导致脂质膜功能障碍，从而引发进一步的下游生化级联反应。然而，脂质过氧化如何调节脂质膜的机械特性仍然存在很大争议。在这项研究中，我们使用分子动力学模拟研究了具有多不饱和脂肪酸尾部的脂质的过氧化。通过系统地改变氧化位点，我们发现脂质过氧化以过氧化位点特异性方式改变双层膜的生物物理特性。具体而言，我们的结果表明，双层内部部位的过氧化会扰乱和软化膜，而膜 - 水界面附近部位的过氧化会导致膜更加有序和坚硬。这种脂质膜力学的过氧化位点特异性调节为先前实验中获得的相互矛盾的结果提供了解释。我们的研究为更好地理解由脂质过氧化引起的下游细胞功能障碍的发生铺平了道路。而膜-水界面附近位置的过氧化导致更有序和更硬的膜。这种脂质膜力学的过氧化位点特异性调节为先前实验中获得的相互矛盾的结果提供了解释。我们的研究为更好地理解由脂质过氧化引起的下游细胞功能障碍的发生铺平了道路。而膜-水界面附近位置的过氧化导致更有序和更硬的膜。这种脂质膜力学的过氧化位点特异性调节为先前实验中获得的相互矛盾的结果提供了解释。我们的研究为更好地理解由脂质过氧化引起的下游细胞功能障碍的发生铺平了道路。