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Probing the Action of Cytochrome c Oxidase

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The Structural Basis of Biological Energy Generation

Part of the book series: Advances in Photosynthesis and Respiration ((AIPH,volume 39))

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Summary

Density functional theory (DFT) and combined Molecular Mechanics/Quantum Mechanics (MM/QM-MD) calculations have been applied to models of the cytochrome c oxidase (CcO) including the Fe–CuB binuclear center, where dioxygen is bound and subsequently reduced to water. The properties of several intermediates of the CcO dioxygen reaction have been investigated by theoretical approaches. In this chapter, we investigate the dynamics of the binuclear heme Fe–CuB throughout the O2 catalytic cycle. We are focused on the effects of the protein matrix and proton/water motion exerted on the heme a 3 group. For this, we have built models of CcO, which vary at the heme a 3 environment. This variability is based on hydrogen bonding interactions and amino acid protonation states. Different control points have been identified for the transition from one intermediate to the next. The hydrogen bonding networks in the proximity of heme a 3 area also have consequences for the characteristics of the binuclear center. A theoretical framework for the direct link between an H+ delivery channel (termed D) and an accumulation of waters, termed ‘water pool’ close to the active site, has been achieved at the QM/MM level of theory. Two proton valves (E278 and His403) and an electron/proton coupling site (propionate-A/Asp399) exist in this pathway for the aa 3 CcO from P. denitrificans. The ferryl intermediate, produced subsequent to the O–O bond scission, is found to have characteristics highly dependent on the basicity of the proximal His411, in contrast to the hydroxyl intermediate that is sensitive to distal effects.

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Abbreviations

BLYP:

– Functional to describe the exchange and correlation part of the electron-electron interaction energy in the theoretical calculations based on Becke’s correlation functional; Lee, Yang, Parr exchange terms;

CcO:

– Cytochrome c oxidase;

DFT:

– Density functional theory;

MD:

– Molecular dynamics;

MM:

– Molecular mechanics;

OPLS:

– Optimized potentials for liquid simulations force field;

QM:

– Quantum mechanics;

riBLYP:

– Resolution of identity (ri) methodology is an approximation to the computation of two-electron four-center integrals with significantly improved time efficiency;

TZVP:

– Triple-zeta basis sets, TZVP contains a set of d-functions on the heavy atoms and one set of p-functions on hydrogen atoms

References

  • Babcock GT, Wikström M (1992) Oxygen activation and the conservation of energy in cell respiration. Nature 356:301–309

    Article  CAS  PubMed  Google Scholar 

  • Bassan A, Blomberg MRA, Borowski T, Siegbahn PEM (2006) Theoretical studies of enzyme mechanisms involving high-valent iron intermediates. J Inorg Biochem 100:727–743

    Article  CAS  PubMed  Google Scholar 

  • Belevich I, Verkhovsky MI (2008) Molecular mechanism of proton translocation by cytochrome c oxidase. Antiox Redox Signal 10:1–30

    Article  CAS  Google Scholar 

  • Bellevich I, Verkhovsky MI, Wikström M (2006) Proton-coupled electron transfer drives the proton pump of cytochrome c oxidase. Nature 440:829–832

    Article  Google Scholar 

  • Billingsley FP, Bloor JE (1971) Limited Expansion of Diatomic Overlap (LEDO): a near-accurate approximate ab initio LCAO MO method. I. Theory and preliminary investigations. J Chem Phys 55:5178–5190

    Article  CAS  Google Scholar 

  • Blomberg MRA, Siegbahn PEM, Babcock GT, Wikström M (2000a) O-O bond splitting mechanism in cytochrome c oxidase. J Inorg Biochem 80:261–269

    Article  CAS  PubMed  Google Scholar 

  • Blomberg MRA, Siegbahn PEM, Babcock GT, Wikström M (2000b) Modeling cytochrome oxidase – a quantum chemical study of the O-O bond cleavage mechanism. J Am Chem Soc 122:12848–12858

    Article  CAS  Google Scholar 

  • Blomberg MRA, Siegbahn PEM, Babcock GT (2003) Metal-bridging mechanism for O-O bond cleavage in cytochrome C oxidase. Inorg Chem 42:5231–5243

    Article  CAS  PubMed  Google Scholar 

  • Crane BR, Siegel LM, Getzoff ED (1997) Structures of the siroheme- and Fe4S4-containing active center of sulfite reductase in different states of oxidation: heme activation via reduction-gated exogenous ligand exchange. Biochemistry 36:12101–12119

    Article  CAS  PubMed  Google Scholar 

  • Daskalakis V, Farantos SC, Varotsis C (2008) Assigning vibrational spectra of ferryl-oxo ontermediates of cytochrome c oxidase by periodic orbits and molecular dynamics. J Am Chem Soc 130:12385–12393

    Article  CAS  PubMed  Google Scholar 

  • Daskalakis V, Farantos SC, Guallar V, Varotsis C (2010) Vibrational resonances and CuB displacement controlled by proton motion in cytochrome c oxidase. J Phys Chem B 114:1136–1143

    Article  CAS  PubMed  Google Scholar 

  • Daskalakis V, Farantos SC, Guallar V, Varotsis C (2011) Regulation of electron and proton transfer by the protein matrix of cytochrome c oxidase. J Phys Chem B 115:3648–3655

    Article  CAS  PubMed  Google Scholar 

  • Decatur SM, Belcher KL, Rickert PK, Franzen S, Boxer SG (1999) Hydrogen bonding modulates binding of exogenous ligands in a myoglobin proximal cavity mutant. Biochemistry 38:11086–11092

    Article  CAS  PubMed  Google Scholar 

  • Eichkorn K, Treutler O, Öhm H, Häser M, Ahlrichs R (1995) Auxiliary basis-sets to approximate coulomb potentials. Chem Phys Lett 240:283–289

    Article  CAS  Google Scholar 

  • Ferguson-Miller S, Babcock GT (1996) Heme/copper terminal oxidases. Chem Rev 96:2889–2908

    Article  CAS  PubMed  Google Scholar 

  • Gennis RB (1998) Multiple proton-conducting pathways in cytochrome oxidase and a proposed role for the active-site tyrosine. Biochim Biophys Acta 1365:241–248

    Article  CAS  Google Scholar 

  • Goodin DB, McRee DE (1993) The Asp-His-iron triad of cytochrome c peroxidase controls the reduction potential electronic structure, and coupling of the tryptophan free radical to the heme. Biochemistry 32:3313–3324

    Article  CAS  PubMed  Google Scholar 

  • Han S, Ching YC, Rousseau DL (1989) Evidence for a hydroxide intermediate in cytochrome c oxidase. J Biol Chem 264:6604–6607

    CAS  PubMed  Google Scholar 

  • Han S, Takahashi S, Rousseau DL (2000) Time-dependence of the catalytic intermediates in cytochrome c oxidase. J Biol Chem 275:1910–1919

    Article  CAS  PubMed  Google Scholar 

  • Hunsicker-Wang LM, Pacoma RL, Chen Y, Fee JA, Stout CD (2005) A novel cryoprotection scheme for enhancing the diffraction of crystals of recombinant cytochrome ba3 oxidase from Thermus thermophiles. Acta Crystallogr Sect D 61:340–343

    Article  Google Scholar 

  • Iwata S, Ostermeier C, Ludwig B, Michel H (1995) Structure at 2.8 Å resolution of cytochrome c oxidase from Paracoccus denitrificans. Nature 376:660–669

    Article  CAS  PubMed  Google Scholar 

  • Koepke J, Olkhova E, Angerer H, Müller H, Peng G, Michel H (2009) High resolution crystal structure of Paracoccus denitrificans cytochrome c oxidase: new insights into the active site and the proton transfer pathways. Biochim Biophys Acta 1787:635–645

    Article  CAS  PubMed  Google Scholar 

  • Kozlowski PM, Kuta J, Ohta T, Kitagawa T (2006) Resonance Raman enhancement of Fe–IV=O stretch in high-valent iron porphyrins: an insight from TD-DFT calculations. J Inorg Biochem 100:744–750

    Article  CAS  PubMed  Google Scholar 

  • Michel H (1998a) The mechanism of proton pumping by cytochrome c oxidase. Proc Natl Acad Sci USA 95:12819–12824

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Michel H (1998b) Cytochrome c oxidase: catalytic cycle and mechanisms of proton pumping – a discussion. Biochemistry 38:15129–15140

    Article  Google Scholar 

  • Michel H, Behr J, Harrenga A, Kannt A (1998) Cytochrome c oxidase: structure and spectroscopy. Ann Rev Biophys Biom Struct 27:329–356

    Article  CAS  Google Scholar 

  • Ogura T, Hirota S, Proshlyakov DA, Shinzawa-Itoh K, Yoshikawa S, Kitagawa T (1996) Time-resolved resonance Raman rvidence for tight coupling between electron transfer and proton pumping of cytochrome c oxidase upon the change from the FeV oxidation level to the FeIV oxidation level. J Am Chem Soc 118:5443–5449

    Article  CAS  Google Scholar 

  • Olkhova E, Hutter C, Lill MA, Helms V, Michel H (2004) Dynamic water networks in cytochrome c oxidase from Paracoccus denitrificans investigated by molecular dynamics simulations. Biophys J 86:1873–1889

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ostermeier C, Harrenga A, Ermler U, Michel H (1997) Structure at 2.7 Å resolution of the Paracoccus denitrificans two-subunit cytochrome c oxidase complexed with an antibody FV fragment. Proc Natl Acad Sci USA 94:10547–10553

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pinakoulaki E, Daskalakis V, Ohta T, Richter O-MH, Budiman K, Kitagawa T, Ludwig B, Varotsis C (2013) The structure of two ferryl-oxo intermediates at the same oxidation level in the heme-copper binuclear center of cytochrome c oxidase: the protein effect. J Biol Chem 288:20261–20266

    Article  CAS  PubMed  Google Scholar 

  • Puustinen A, Bailey JA, Dyer RB, Mecklenburg SL, Wikström M, Woodruff WH (1997) Fourier transform infrared evidence for connectivity between CuB and glutamic acid 286 in cytochrome bo3 from Escherichia coli. Biochemistry 36:13195–13200

    Article  CAS  PubMed  Google Scholar 

  • Rauhamäki V, Baumann M, Soliymani R, Puustinen A, Wikström M (2006) Identification of a histidine-tyrosine cross-link in the active site of the cbb3-type cytochrome c oxidase from Rhodobacter sphaeroides. Proc Natl Acad Sci USA 103:16135–16140

    Article  PubMed Central  PubMed  Google Scholar 

  • Riistama S, Hummer G, Puustinen A, Dyer RB, Woodruff WH, Wikström M (1997) Bound water in the proton translocation mechanism of the haem-copper oxidases. FEBS Lett 414:275–280

    Article  CAS  PubMed  Google Scholar 

  • Schmidt B, McCracken J, Ferguson-Miller S (2003) A discrete water exit pathway in the membrane protein cytochrome c oxidase. Proc Natl Acad Sci USA 100:15539–15542

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schrodinger Suite of Programs (2010) http://www.schrodinger.com

  • Soulimane T, Buse G, Bourenkov GP, Bartunik HD, Huber R, Than ME (2000) Structure and mechanism of the aberrant ba3-cytochrome c oxidase from Thermus thermophilus. EMBO J 19:1766–1776

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tsukihara T, Aoyama H, Yamashita E, Tomizaki T, Yamaguchi H, Shinzawa-Itoh K, Nakashima R, Yaono R, Yoshikawa S (1995) Structure of metal sites of oxidized bovine heart cytochrome c oxidase at 2.8 Å resolution. Science 269:1069–1074

    Article  CAS  PubMed  Google Scholar 

  • Turbomole V5–8–0 24 Nov. 2005, University of Karlsruhe

    Google Scholar 

  • Varotsis C, Babcock GT (1990) Appearance of the ν(FeIV=O) vibration from a ferryl-oxo intermediate in the cytochrome oxidase/dioxygen reaction. Biochemistry 29:7357–7362

    Article  CAS  PubMed  Google Scholar 

  • Vogel KM, Spiro TG, Shelver D, Thorsteinsson MV, Roberts GP (1999) Resonance Raman evidence for a novel charge relay activation mechanism of the CO-dependent heme protein transcription factor CooA. Biochemistry 38:2679–2687

    Article  CAS  PubMed  Google Scholar 

  • Wikström M (1981) Energy-dependent reversal of the cytochrome oxidase reaction. Proc Natl Acad Sci USA 78:4051–4054

    Article  PubMed Central  PubMed  Google Scholar 

  • Wikström M (1989) Identification of the electron transfers in cytochrome oxidase that are coupled to proton-pumping. Nature 338:776–778

    Article  PubMed  Google Scholar 

  • Wikström M, Ribacka C, Molin M, Laakkonen L, Verkhovsky M, Puustinen A (2005) Gating of proton and water transfer in the respiratory enzyme cytochrome c oxidase. Proc Natl Acad Sci USA 102:10478–10481

    Article  PubMed Central  PubMed  Google Scholar 

  • Xu J, Voth GA (2005) Computer simulation of explicit proton translocation in cytochrome c oxidase. Proc Natl Acad Sci USA 102:6795–6800

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yoshikawa S, Shinzawa-Itoh K, Tsukihara T (1998) Crystal structure of bovine heart cytochrome c oxidase at 2.8 A resolution. J Bioenerg Biomembr 30:7–14

    Article  CAS  PubMed  Google Scholar 

  • Zheng X, Medvedev DM, Swanson J, Stuchebrukhov AA (2003) Computer simulation of water in cytochrome c oxidase. Biochim Biophys Acta 1557:99–107

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

All calculations have been performed either at the Institute of Electronic Structure and Laser of the Foundation for Research and Technology – Hellas (IESL-FORTH), the Barcelona Supercomputing Center (BSC) at the Life Sciences Department, at the Supercomputing Center in Okazaki National Research Institutes and the European GRID infrastructure (EGEE).

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Authors and Affiliations

  1. Department of Environmental Science and Technology, Cyprus University of Technology, 50329, 3603, Lemesos, Cyprus

    Vangelis Daskalakis & Constantinos Varotsis

Authors
  1. Vangelis Daskalakis
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  2. Constantinos Varotsis
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Correspondence to Constantinos Varotsis .

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Editors and Affiliations

  1. Department of Biotechnology, Norwegian University of Science and Technology, Trondheim, Sør-Trøndelag Fylke, Norway

    Martin F. Hohmann-Marriott

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Daskalakis, V., Varotsis, C. (2014). Probing the Action of Cytochrome c Oxidase. In: Hohmann-Marriott, M. (eds) The Structural Basis of Biological Energy Generation. Advances in Photosynthesis and Respiration, vol 39. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8742-0_10

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