title: Proton-coupled electron transfer and the role of water molecules in proton pumping by cytochrome c oxidase.
abstract: Molecular oxygen acts as the terminal electron sink in the respiratory chains of aerobic organisms. Cytochrome c oxidase in the inner membrane of mitochondria and the plasma membrane of bacteria catalyzes the reduction of oxygen to water, and couples the free energy of the reaction to proton pumping across the membrane. The proton-pumping activity contributes to the proton electrochemical gradient, which drives the synthesis of ATP. Based on kinetic experiments on the O-O bond splitting transition of the catalytic cycle (A → P(R)), it has been proposed that the electron transfer to the binuclear iron-copper center of O2 reduction initiates the proton pump mechanism. This key electron transfer event is coupled to an internal proton transfer from a conserved glutamic acid to the proton-loading site of the pump. However, the proton may instead be transferred to the binuclear center to complete the oxygen reduction chemistry, which would constitute a short-circuit. Based on atomistic molecular dynamics simulations of cytochrome c oxidase in an explicit membrane-solvent environment, complemented by related free-energy calculations, we propose that this short-circuit is effectively prevented by a redox-state-dependent organization of water molecules within the protein structure that gates the proton transfer pathway.
authors: Department of Physics, Tampere University of Technology, FI-33101, Tampere, Finland; vivek.sharma@tut.fi marten.wikstrom@helsinki.fi.
authors: Vivek
authors: V
authors: Sharma
authors: Department of Physics, Tampere University of Technology, FI-33101, Tampere, Finland;
authors: Giray
authors: G
authors: Enkavi
authors: Department of Physics, Tampere University of Technology, FI-33101, Tampere, Finland; MEMPHYS - Center for Biomembrane Physics, Department of Physics, University of Southern Denmark, DK-5230, Odense, Denmark; and.
authors: Ilpo
authors: I
authors: Vattulainen
authors: Department of Physics, Tampere University of Technology, FI-33101, Tampere, Finland;
authors: Tomasz
authors: T
authors: Róg
authors: Helsinki Bioenergetics Group, Programme for Structural Biology and Biophysics, Institute of Biotechnology, University of Helsinki, FI-00014, Helsinki, Finland vivek.sharma@tut.fi marten.wikstrom@helsinki.fi.
authors: Mårten
authors: M
authors: Wikström
mesh_terms: D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011522:Protons; D014867:Water / Q000737:chemistry*
chemical_list: D011522:Protons; D014867:Water; D003576:Electron Transport Complex IV
keywords: atomistic molecular dynamics simulations; cell respiration; free-energy calculations; functional water molecules
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