Husen Peter, Solov'yov Ilia A
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark.
Department of Physics, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany.
Front Chem. 2021 May 19;9:643796. doi: 10.3389/fchem.2021.643796. eCollection 2021.
Much of the metabolic molecular machinery responsible for energy transduction processes in living organisms revolves around a series of electron and proton transfer processes. The highly redox active enzymes can, however, also pose a risk of unwanted side reactions leading to reactive oxygen species, which are harmful to cells and are a factor in aging and age-related diseases. Using extensive quantum and classical computational modeling, we here show evidence of a particular superoxide production mechanism through stray reactions between molecular oxygen and a semiquinone reaction intermediate bound in the mitochondrial complex III of the electron transport chain, also known as the cytochrome complex. Free energy calculations indicate a favorable electron transfer from semiquinone occurring at low rates under normal circumstances. Furthermore, simulations of the product state reveal that superoxide formed at the Q -site exclusively leaves the complex at the positive side of the membrane and escapes into the intermembrane space of mitochondria, providing a critical clue in further studies of the harmful effects of mitochondrial superoxide production.
负责生物体内能量转导过程的许多代谢分子机制都围绕着一系列电子和质子转移过程。然而，具有高度氧化还原活性的酶也可能引发不必要的副反应，导致活性氧的产生，而活性氧对细胞有害，是衰老和与年龄相关疾病的一个因素。通过广泛的量子和经典计算建模，我们在此展示了一种特定的超氧化物产生机制的证据，该机制是通过分子氧与结合在电子传递链线粒体复合物III（也称为细胞色素复合物）中的半醌反应中间体之间的杂散反应产生的。自由能计算表明，在正常情况下，半醌发生的电子转移速率较低，但却是有利的。此外，产物状态的模拟显示，在Q-位点形成的超氧化物仅在线粒体膜的正侧离开复合物，并逸入线粒体的膜间隙，这为进一步研究线粒体超氧化物产生的有害影响提供了关键线索。
