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Redox-induced activation of the proton pump in the respiratory complex I

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Hummer,  Gerhard
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Sharma, V., Belevich, G., Gamiz-Hernandez, A. P., Róg, T., Vattulainen, I., Verkhovskaya, M. L., et al. (2017). Redox-induced activation of the proton pump in the respiratory complex I. Proceedings of the National Academy of Sciences of the United States of America, 112(37), 11571-11576. doi:10.1073/pnas.1503761112.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002A-47E7-E
Abstract
Complex I functions as a redox-linked proton pump in the respiratory chains of mitochondria and bacteria, driven by the reduction of quinone (Q) by NADH. Remarkably, the distance between the Q reduction site and the most distant proton channels extends nearly 200 Å. To elucidate the molecular origin of this long-range coupling, we apply a combination of large-scale molecular simulations and a site-directed mutagenesis experiment of a key residue. In hybrid quantum mechanics/molecular mechanics simulations, we observe that reduction of Q is coupled to its local protonation by the His-38/Asp-139 ion pair and Tyr-87 of subunit Nqo4. Atomistic classical molecular dynamics simulations further suggest that formation of quinol (QH2) triggers rapid dissociation of the anionic Asp-139 toward the membrane domain that couples to conformational changes in a network of conserved charged residues. Site-directed mutagenesis data confirm the importance of Asp-139; upon mutation to asparagine the Q reductase activity is inhibited by 75%. The current results, together with earlier biochemical data, suggest that the proton pumping in complex I is activated by a unique combination of electrostatic and conformational transitions.