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bioRxiv · 10.1101/2024.09.06.611712

Catalytic relevance of quinol anion in biological energy conversion by respiratory complex I

Zdorevskyi, O.·Laukkanen, J.·Sharma, V.
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Abstract

Redox chemistry of quinones is an essential component of life on earth. In the mitochondrial electron transport chain, ubiquinone molecule is reduced to ubiquinol by respiratory complex I to drive the synthesis of ATP. By performing both classical and hybrid QM/MM simulations on high-resolution cryo-EM structures, including quantitative free energy calculations, we show that semiquinone species in complex I is anionic in nature and is trapped in the active site chamber for its subsequent reduction. Two-electron reduction of ubiquinone yields a metastable ubiquinol anion, which is electrostatically pushed by 15-20 [A] towards the exit of the ubiquinone binding chamber to drive the proton pump of complex I. As part of the two-electron reduction of ubiquinone, protonic rearrangements take place in the active site in which a highly conserved histidine converts from its one tautomeric state to another. The combined findings provide a detailed and testable mechanistic picture of proton-coupled electron transfer reaction at the active site of complex I in wild-type as well as mutant conditions.

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Zdorevskyi, O., Laukkanen, J., Sharma, V.. 2024-09-07. Catalytic relevance of quinol anion in biological energy conversion by respiratory complex I. https://doi.org/10.1101/2024.09.06.611712

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