Chng Choon-Peng, Sadovsky Yoel, Hsia K Jimmy, Huang Changjin
School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore 639798, Republic of Singapore.
Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Extreme Mech Lett. 2021 Jan;42. doi: 10.1016/j.eml.2020.101148. Epub 2020 Dec 14.
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.
质膜的过氧化作用，其特征是对不饱和脂肪酸中脂质碳 - 碳双键的氧化攻击，已被确定为多种病理状况下的一个重要生化事件，这些病理状况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。脂质过氧化作用导致的脂质双层结构变化可能会引起脂质膜功能异常，并进而引发进一步的下游生化级联反应。然而，脂质过氧化作用如何调节脂质膜的力学性质在很大程度上仍存在争议。在本研究中，我们使用分子动力学模拟来研究具有多不饱和脂肪酸尾部的脂质的过氧化作用。通过系统地改变氧化位点，我们发现脂质过氧化作用以一种氧化位点特异性的方式改变双层膜的生物物理性质。具体而言，我们的结果表明，双层膜内部位点的过氧化作用会扰乱并软化膜，而膜 - 水界面附近位点的过氧化作用则导致膜更加有序且更硬。脂质膜力学性质的这种氧化位点特异性调节为先前实验中获得的矛盾结果提供了解释。我们的研究为更好地理解脂质过氧化作用引发的下游细胞功能障碍奠定了基础。
