Sharma V 2015 Proc Natl Acad Sci U S A
| Sharma V, Belevich G, Gamiz-Hernandez AP, Róg T, Vattulainen I, Verkhovskaya ML, Wikström M, Hummer G, Kaila VR (2015) Redox-induced activation of the proton pump in the respiratory Complex I. Proc Natl Acad Sci U S A 112:11571-6. https://doi.org/10.1073/pnas.1503761112 |
Sharma Vivek, Belevich G, Gamiz-Hernandez AP, Rog T, Vattulainen I, Verkhovskaya ML, Wikstroem Marten KF, Hummer G, Kaila Ville R (2015) Proc Natl Acad Sci U S A
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.
• Bioblast editor: Gnaiger E
Labels:
Preparation: Enzyme
Enzyme: Complex I
Quantum biology
