Modeling the Energy Landscape of Side Reactions in the Cytochrome bc1 Complex
Peter Husen, Ilia A. Solov'yov
Frontiers in Chemistry
Much of the metabolic molecular machinery responsible for energy transductionprocesses 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 bc1 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 Qo-site exclusively leaves the bc1 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.