Electrostatics, hydration, and proton transfer dynamics in the membrane domain of respiratory complex I.
Complex I serves as the primary electron entry point into the mitochondrial and bacterial respiratory chains. It catalyzes the reduction of quinones by electron transfer from NADH, and couples this exergonic reaction to the translocation of protons against an electrochemical proton gradient. The membrane domain of the enzyme extends ∼180 Å from the site of quinone reduction to the most distant proton pathway. To elucidate possible mechanisms of the long-range proton-coupled electron transfer process, we perform large-scale atomistic molecular dynamics simulations of the membrane domain of complex I from Escherichia coli. We observe spontaneous hydration of a putative proton entry channel at the NuoN/K interface, which is sensitive to the protonation state of buried glutamic acid residues. In hybrid quantum mechanics/classical mechanics simulations, we find that the observed water wires support rapid proton transfer from the protein surface to the center of the membrane domain. To explore the functional relevance of the pseudosymmetric inverted-repeat structures of the antiporter-like subunits NuoL/M/N, we constructed a symmetry-related structure of a possible alternate-access state. In molecular dynamics simulations, we find the resulting structural changes to be metastable and reversible at the protein backbone level. However, the increased hydration induced by the conformational change persists, with water molecules establishing enhanced lateral connectivity and pathways for proton transfer between conserved ionizable residues along the center of the membrane domain. Overall, the observed water-gated transitions establish conduits for the unidirectional proton translocation processes, and provide a possible coupling mechanism for the energy transduction in complex I.
Department Chemie, Technische Universität München, D-85748 Garching, Germany;Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520; ville.kaila@ch.tum.de gerhard.hummer@biophys.mpg.de.
Ville R I
VR
Kaila
Helsinki Bioenergetics Group, Institute of Biotechnology, University of Helsinki, FI-00014 Helsinki, Finland; and.
Mårten
M
Wikström
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520;Department of Theoretical Biophysics, Max Planck Institute of Biophysics, 60438 Frankfurt am Main, Germany ville.kaila@ch.tum.de gerhard.hummer@biophys.mpg.de.
Gerhard
G
Hummer
D004563:Electrochemistry; D004579:Electron Transport / Q000502:physiology; D042967:Electron Transport Complex I / Q000737:chemistry* / Q000378:metabolism*; D004926:Escherichia coli / Q000737:chemistry* / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009245:NADH Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011522:Protons; D014867:Water / Q000737:chemistry
D029968:Escherichia coli Proteins; D008565:Membrane Proteins; C098483:NADH dehydrogenase subunit 4; C000589385:NuoN protein, E coli; D011522:Protons; D014867:Water; D009245:NADH Dehydrogenase; C479743:NuoL protein, E coli; C476247:NuoM protein, E coli; D042967:Electron Transport Complex I
Grotthuss mechanism; QM/MM; biological energy conversion; proton pumping