Abstract
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 Qo-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.
Highlights
The cytochrome bc1 complex is a transmembrane protein complex in the inner mitochondrial membrane of eukaryotes or the plasma membrane of photosynthetically active bacteria
We discuss the results from quantum chemical modeling of a region around the Qo-site with O2 bound, where we generate statistics of local spin densities and identify possible chemical reactions leading to superoxide production
We estimate the possible superoxide production rate based on the free energy results
Summary
The cytochrome bc complex is a transmembrane protein complex in the inner mitochondrial membrane of eukaryotes or the plasma membrane of photosynthetically active bacteria. It was previously shown (Husen and Solov’yov, 2016, Husen and Solov’yov, 2017) that O2 molecules can occasionally enter the protein complex through the membrane and become trapped close to the iron-sulfur cluster (Fe2S2) at the Qo binding site of the bc complex during a short-lived state of the Q-cycle, in which a bound QH2 has been partly oxidized to a semiquinone anion (Q−) at the Qo-site (Crofts et al, 2003; Barragan et al, 2016) As this reaction intermediate is a radical, it is conceivable that it could react with a nearby oxygen molecule to produce a potentially harmful superoxide anion, O2−
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