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.
journal_name
Proc Natl Acad Sci U S Aauthors
Sharma V,Belevich G,Gamiz-Hernandez AP,Róg T,Vattulainen I,Verkhovskaya ML,Wikström M,Hummer G,Kaila VRdoi
10.1073/pnas.1503761112subject
Has Abstractpub_date
2015-09-15 00:00:00pages
11571-6issue
37eissn
0027-8424issn
1091-6490pii
1503761112journal_volume
112pub_type
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