Journal of Chemical Information and Modeling
Reactive oxygen species such as superoxide are potentially harmful byproducts ofthe aerobic metabolism in the inner mitochondrial membrane, and complexes I, II, III of the electrontransport chain have been identified as primary sources. The mitochondrial fatty acid b-oxidation pathway may also play a yet uncharacterized role in reactive oxygen species generation, apparently at the level of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) and/or its redox partner electron-transfer flavoprotein (ETF). These enzymes comprise a key pathway through which electrons are sequentially shuttled from several dehydrogenases to the respiratory chain. The exact mechanisms of superoxide production have not been fully established, but a crucial starting point would be the binding of molecular oxygen within one of the protein complexes. The present investigation offers a comprehensive computational approach for the determination of binding modes and characteristic binding times of small molecules inside proteins, which is then used to reveal several O2 binding sites near the flavin adenine dinucleotide cofactor of the ETF enzyme. The binding sites are further characterized to extract the necessary parameters for further studies of possible electron transfer between flavin and O2 leading to radical pair formation and possible superoxide production.