title: Role of subunit III and its lipids in the molecular mechanism of cytochrome c oxidase.
abstract: The terminal respiratory enzyme cytochrome c oxidase (CcO) reduces molecular oxygen to water, and pumps protons across the inner mitochondrial membrane, or the plasma membrane of bacteria. A two-subunit CcO harbors all the elements necessary for oxygen reduction and proton pumping. However, it rapidly undergoes turnover-induced irreversible damage, which is effectively prevented by the presence of subunit III and its tightly bound lipids. We have performed classical atomistic molecular dynamics (MD) simulations on a three-subunit CcO, which show the formation of water wires between the polar head groups of lipid molecules bound to subunit III and the proton uptake site Asp91 (Bos taurus enzyme numbering). Continuum electrostatic calculations suggest that these lipids directly influence the proton affinity of Asp91 by 1-2pK units. We surmise that lipids bound to subunit III influence the rate of proton uptake through the D-pathway, and therefore play a key role in preventing turnover-induced inactivation. Atomistic MD simulations show that subunit III is rapidly hydrated in the absence of internally bound lipids, which is likely to affect the rate of O2 diffusion into the active-site. The role of subunit III with its indigenous lipids in the molecular mechanism of CcO is discussed.
authors.affiliation: Department of Physics, Tampere University of Technology, FI-33101 Tampere, Finland. Electronic address: vivek.sharma@tut.fi.
authors.forename: Vivek
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Department of Physics, Tampere University of Technology, FI-33101 Tampere, Finland.
authors.forename: Pauliina
authors.initials: P
authors.lastname: Ala-Vannesluoma
authors.affiliation: Department of Physics, Tampere University of Technology, FI-33101 Tampere, Finland; MEMPHYS, Center for Biomembrane Physics, Department of Physics, University of Southern Denmark, Odense, Denmark.
authors.forename: Ilpo
authors.initials: I
authors.lastname: Vattulainen
authors.affiliation: Helsinki Bioenergetics Group, Programme for Structural Biology and Biophysics, Institute of Biotechnology, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Mårten
authors.initials: M
authors.lastname: Wikström
authors.affiliation: Department of Physics, Tampere University of Technology, FI-33101 Tampere, Finland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Róg
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D003576:Electron Transport Complex IV / Q000737:chemistry* / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D021122:Protein Subunits; D017494:Proton Pumps; D012242:Rhodobacter sphaeroides / Q000201:enzymology
chemical_list: D008055:Lipids; D021122:Protein Subunits; D017494:Proton Pumps; D003576:Electron Transport Complex IV; D010100:Oxygen
keywords: Cardiolipin; Continuum electrostatic; Molecular dynamics simulation; Oxygen diffusion; Water molecule