Yadav Dharmendra K, Kumar Surendra, Choi Eun-Ha, Sharma Praveen, Misra Sanjeev, Kim Mi-Hyun
College of Pharmacy, Gachon University of Medicine and Science, Incheon, South Korea.
Gachon Institute of Pharmaceutical Science & Department of Pharmacy, College of Pharmacy, Gachon University, Incheon, South Korea.
Front Pharmacol. 2018 Jun 27;9:644. doi: 10.3389/fphar.2018.00644. eCollection 2018.
In recent years, the role of reactive oxygen species (ROS) in regulating cancer cell apoptosis, inflammation, cell ischemia, and cell signaling pathways has been well established. The most common sources of intracellular ROS are the mitochondrial electron transport system, NADH oxidase, and cytochrome P450. In this study, we investigated the dynamics and permeability of ROS using molecular dynamics (MD) simulations on native skin-lipid bilayer membranes. Native skin-lipid bilayers are composed of ceramide, cholesterol, and free fatty acid in an almost equal molar ratio (1:1:1). Dynamic distribution studies on ROS, i.e., hydrogen peroxide (HO) and O (O by analogy), revealed that these species interact with cholesterol as a primary target in lipid peroxidation of the skin-lipid bilayer. Moreover, the permeability of ROS, i.e., HO, hydroxyl radicals (HO), hydroperoxy radical (HOO), and O, along the skin-lipid bilayer was measured using free energy profiles (FEPs). The FEPs showed that in spite of high-energy barriers, ROS traveled through the membrane easily. Breaching the free energy barriers, these ROS permeated into the membrane, inflicting oxidative stress, and causing apoptosis. Collectively, the insight acquired from simulations may result in a better understanding of oxidative stress at the atomic level.
近年来，活性氧（ROS）在调节癌细胞凋亡、炎症、细胞缺血和细胞信号通路中的作用已得到充分证实。细胞内ROS最常见的来源是线粒体电子传递系统、NADH氧化酶和细胞色素P450。在本研究中，我们使用分子动力学（MD）模拟对天然皮肤脂质双层膜研究了ROS的动力学和渗透性。天然皮肤脂质双层由神经酰胺、胆固醇和游离脂肪酸以几乎相等的摩尔比（1:1:1）组成。对ROS（即过氧化氢（HO）和类似的O）的动态分布研究表明，这些物质在皮肤脂质双层的脂质过氧化过程中作为主要靶点与胆固醇相互作用。此外，使用自由能分布（FEP）测量了ROS（即HO、羟基自由基（HO）、氢过氧自由基（HOO）和O）沿皮肤脂质双层的渗透性。FEP表明，尽管存在高能垒，ROS仍能轻松穿过膜。突破自由能垒后，这些ROS渗透到膜中，造成氧化应激并导致细胞凋亡。总的来说，从模拟中获得的见解可能有助于在原子水平上更好地理解氧化应激。
