The proposed work involves density functional theory (DFT) calculations of geometric and electronic structure, electrostatics calculations, and quantum mechanics molecular mechanics molecular dynamics (QM/MM/MD) simulations to provide a detailed mechanistic understanding of the catalytic reaction pathways in B-type cytochrome c oxidases, comparing also to A-type cytochrome c oxidases (CcO's).
Aim 1. To develop a quantum/electrostatic model explaining how chemical bonding and proton/electron flow to molecular oxygen within the Fe-Cu dinuclear complex (DNC) leads to proton pumping across the membrane. QM/MM/MD studies will provide insights into dynamic processes of proton transfer within and the proton exit channel from the DNC.
Aim 2. Detection and characterization of peroxo bridged Fe-Cu species will be related to corresponding electronic states from DFT. DFT calculations of vibrational spectra and other electronic properties (Mossbauer and optical) will be performed for comparisons with experimental spectroscopies.
Aim 3. The K-pathway for proton transfer into the dinuclear Fe-Cu complex will be analyzed using DFT/electrostatics and QM/MM/MD methods.
Aim 4. We will further develop current methodologies to improve the quality of DFT calculations for these large active site models, to analyze dynamic processes with QM/MM/MD, and for the physical description of the remaining protein/membrane/aqueous solvent environment. Cytochrome c oxidase (Complex IV) of mitochondria links electron transfer through the electron transport chain to proton pumping across the inner membrane of the mitochondria, and similarly, across the plasma membrane in most aerobic bacteria. This is the proton motive force utilized for ATP production. Mitochondrial CcO's play an essential role in human health because adequate ATP supplies are required for most important metabolic functions. Also, disruptions in electron or proton transfer reactions or oxygen binding at CcO can lead the production of damaging reactive oxygen species including hydroxyl and superoxide radicals, and hydrogen peroxide. Understanding the structures, mechanisms, and functions of mitochondrial CcO's is important for better analysis of many genetic and metabolic diseases and cancers, and is also relevant to pathologies of aging.

Public Health Relevance

We are using methods from quantum chemistry, electrostatics, and molecular dynamics to obtain a detailed mechanistic understanding of how oxygen binding and electron/proton flow into cytochrome c oxidase leads to proton pumping across the inner membrane of mitochondria in humans, and similarly across the plasma membrane in most aerobic bacteria. The proton motive force generated is used for ATP production, and defects in this enzyme harm energy production, and also can generate reactive radical oxygen species. Defects in mitochondrial metabolism are associated with many metabolic diseases, cancers, and pathologies of aging, so analyzing this molecular machine has great significance.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-N (02))
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Anderson, Vernon
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Scripps Research Institute
La Jolla
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Han Du, Wen-Ge; Götz, Andreas W; Noodleman, Louis (2018) A Water Dimer Shift Activates a Proton Pumping Pathway in the PR ? F Transition of ba3 Cytochrome c Oxidase. Inorg Chem 57:1048-1059
Yang, Longhua; Skjevik, Åge A; Han Du, Wen-Ge et al. (2016) Data for molecular dynamics simulations of B-type cytochrome c oxidase with the Amber force field. Data Brief 8:1209-14
Tabrizi, Shadan Ghassemi; Pelmenschikov, Vladimir; Noodleman, Louis et al. (2016) The Mössbauer Parameters of the Proximal Cluster of Membrane-Bound Hydrogenase Revisited: A Density Functional Theory Study. J Chem Theory Comput 12:174-87
Yang, Longhua; Skjevik, Åge A; Han Du, Wen-Ge et al. (2016) Water exit pathways and proton pumping mechanism in B-type cytochrome c oxidase from molecular dynamics simulations. Biochim Biophys Acta 1857:1594-1606
Han Du, Wen-Ge; Götz, Andreas W; Yang, Longhua et al. (2016) A broken-symmetry density functional study of structures, energies, and protonation states along the catalytic O-O bond cleavage pathway in ba3 cytochrome c oxidase from Thermus thermophilus. Phys Chem Chem Phys 18:21162-71
Blachly, Patrick G; Sandala, Gregory M; Giammona, Debra Ann et al. (2015) Broken-Symmetry DFT Computations for the Reaction Pathway of IspH, an Iron-Sulfur Enzyme in Pathogenic Bacteria. Inorg Chem 54:6439-61
Baranczak, Aleksandra; Liu, Yu; Connelly, Stephen et al. (2015) A fluorogenic aryl fluorosulfate for intraorganellar transthyretin imaging in living cells and in Caenorhabditis elegans. J Am Chem Soc 137:7404-14
Mones, Letif; Jones, Andrew; Götz, Andreas W et al. (2015) The adaptive buffered force QM/MM method in the CP2K and AMBER software packages. J Comput Chem 36:633-48
Han Du, Wen-Ge; Noodleman, Louis (2015) Broken Symmetry DFT Calculations/Analysis for Oxidized and Reduced Dinuclear Center in Cytochrome c Oxidase: Relating Structures, Protonation States, Energies, and Mössbauer Properties in ba3 Thermus thermophilus. Inorg Chem 54:7272-90
Noodleman, Louis; Han Du, Wen-Ge; Fee, James A et al. (2014) Linking chemical electron-proton transfer to proton pumping in cytochrome c oxidase: broken-symmetry DFT exploration of intermediates along the catalytic reaction pathway of the iron-copper dinuclear complex. Inorg Chem 53:6458-72

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