News and Publications

Quantum Bioinorganic Chemistry and Photochemistry

L. Noodleman, D.A. Case, T. Lovell, T. Liu, F. Himo, W.G. Han, M.J. Thompson, R.A. Torres

We use modern methods of quantum chemistry (density functional methods) to investigate the electronic structures, energetics, and spectroscopy of transition-metal complexes at the active sites of metalloproteins. These systems include iron-sulfur and iron-oxo complexes. Many of these complexes lie at the active sites of important metalloproteins, where they are involved in electron transfer and catalysis.

Two important aspects of our work are the extensive use of quantum mechanical geometry optimization for the active-site quantum cluster and the electrostatic representation of complete protein and solvent environments. The protein electrostatics calculations and analysis are done in collaboration with D. Bashford and D. Asthagiri, Department of Molecular Biology. We are also working with their group on studies of the energetics of catalytic dephosphorylation by protein tyrosine phosphatases, enzymes important in cell signaling and regulation.

In collaboration with F. Gryszpan, Department of Molecular Biology, calculations of acidities of substituted phenols were used in the design of haptens to generate catalytic antibodies with phosphatase activity. The goal of this research is the neutralization of nerve gases and insecticide toxins. We also collaborate with K.B. Sharpless, Z. Demko, V. Fokin, and V. Rostovtsev, Department of Chemistry, on the mechanisms of click chemistry and transition-metal catalysis.

In collaboration with E. Getzoff and M. Thompson, Department of Molecular Biology, we are studying photoactive yellow protein. This protein contains a chromophore that undergoes a light cycle and so acts as a protein photosensor. In a related context, following up on experimental work done in the laboratories of R. Lerner, D. Millar, and R. Stevens, Department of Molecular Biology, and in collaboration with F. Salsbury and C. Brooks, also of the Department of Molecular Biology, we are studying the mechanism of the blue fluorescence of stilbene when this molecule is bound to an antibody. Also, with K. Hahn, Department of Cell Biology, we are investigating improvements in organic fluorescent dyes, which can act as reporters of protein conformational changes or reactions in cells.

We calculated electronic structures and optimized geometries for active-site structures of the iron-oxo enzymes methane monooxygenase and ribonucleotide reductase in both the oxidized and the 2-electron reduced forms. We also evaluated related energetics in the protein environment. For the 2-electron reduced forms, a comparative study of geometries and energetics of native ribonucleotide reductase, a mutant ribonucleotide reductase, and native methane monooxygenase indicated how the various alternative conformations of the bridging carboxylate ligand (called the carboxylate shift) arise from different protein environments. These alternative structures constitute a "branch point" for the subsequent reactions with molecular oxygen and so influence the different catalytic chemistries of these enzymes.

Because iron-sulfur proteins are often electron-transfer agents, we seek to understand which features of cluster electronic structure and what interactions with the protein environment determine the wide range of redox potentials in these systems. In some important instances, the redox state and the protonation states of the active site are coupled. The Rieske iron-sulfur protein is an important part of the cytochrome b-c₁ complex, which links electron transfer from ubiquinone to cytochrome c to proton pumping across the inner mitochondrial membrane. In collaboration with G.M. Ullmann, University of Heidelberg, Germany, we used density functional and electrostatics methods to calculate the pH dependence of the redox potential of the Rieske iron-sulfur protein.

We are continuing electronic structure calculations for the iron-molybdenum cofactor of the nitrogenase enzyme. This cofactor is the 7Fe1Mo active site of the iron-molybdenum protein which binds molecular nitrogen and protons and catalyzes the multielectron reduction of molecular nitrogen to 2 ammonia molecules plus molecular hydrogen. We calculated the active-site geometry, electronic structure, energy, and metal spin alignment for some likely cluster oxidation and electronic states. Using observations obtained via Mossbauer spectroscopy, we identified the probable states that correspond to the "resting form" of the enzyme and the likely candidates for the 1-electron reduced and oxidized states. This information is a required starting point for studies of the catalytic cycle of the enzyme.

Manganese, iron, and copper-zinc superoxide dismutases are important detoxifying agents for superoxide radical anions, converting these anions to molecular oxygen and hydrogen peroxide. Recently, we calculated quantum mechanically optimized geometries and redox potentials, including the coupling between electron transfer and proton transfer, for the active sites of manganese and iron superoxide dismutases and compared these with redox potentials derived from reaction kinetics analysis.

PUBLICATIONS

Han, W.G., Lovell, T., Liu, T., Noodleman, L. Density functional studies of the ground-and excited-state potential-energy curves of stilbene cis-trans isomerization. ChemPhysChem 3:167, 2002.

Han, W.G., Lovell T., Noodleman, L. Coupled redox potentials in manganese and iron superoxide dismutases from reaction kinetics and density functional/electrostatics calculations. Inorg. Chem. 41:205, 2002.

Himo, F., Demko, Z.P., Noodleman, L., Sharpless, K.B. Mechanisms of tetrazole formation by addition of azide to nitriles. J. Am. Chem. Soc., in press.

Huang, H., Han, W.G., Noodleman, L., Grynszpan, F. Multiple reactive immunization towards the hydrolysis of organophosphorus nerve agents: hapten design and synthesis. Bioorg. Med. Chem. 9:3185, 2001.

Lovell, T., Han, W.G., Liu, T., Noodleman, L. A structural model for the high-valent intermediate Q of methane monooxygenase from broken-symmetry density functional and electrostatics calculations. J. Am. Chem. Soc. 124:5890, 2002.

Lovell, T., Li, J., Case, D.A., Noodleman, L. Binding modes for the first coupled electron and proton addition to FeMoco of nitrogenase. J. Am. Chem. Soc. 124:4546, 2002.

Lovell, T., Li, J., Liu, T., Case, D.A., Noodleman, L. FeMo cofactor of nitrogenase: a density functional study of states M^N, M^OX, M^R, and M^I. J. Am. Chem. Soc. 123:12392, 2001.

Lovell, T., Li, J., Noodleman, L. Density functional and electrostatics study of oxidized and reduced ribonucleotide reductase: comparisons with methane monooxygenase. J. Biol. Inorg. Chem., in press.

Lovell, T., Li, J., Noodleman, L. Density functional studies of oxidized and reduced methane monooxygenase: optimized geometries and exchange coupling of active site clusters. Inorg. Chem. 40:5251, 2001.

Lovell, T., Li, J., Noodleman, L. Energetics of oxidized and reduced methane monooxygenase active site clusters in the protein environment. Inorg. Chem. 40:5267, 2001.

Lovell, T., Li, J., Noodleman, L. FeMo cofactor of nitrogenase: energetics and local interactions in the protein environment. J. Biol. Inorg. Chem., in press.

Noodleman, L., Lovell, T., Liu, T., Himo, F., Torres, R.A. Insights into properties and energetics of iron-sulfur proteins from simple clusters to nitrogenase. Curr. Opin. Chem. Biol. 6:259, 2002.

Ullmann, G.M., Noodleman, L., Case, D.A. Density functional calculation of pKa values and redox potentials in the bovine Rieske iron-sulfur protein. J. Biol. Inorg. Chem. 7:632, 2002.