News and Publications

Electronic Structure Calculations for Active-Site Models of Iron-Sulfur Proteins and for Biologically Relevant Transition-Metal Complexes

L. Noodleman, D.A. Case, T. Lovell, J. Li, M.E. Stroupe, M.J. Thompson, C.L. Fisher,* D.N. Hendrickson,** M.J. Knapp,*** R. Konecny,**** Z. Chen*****

* Structural Bioinformatics, Inc., San Diego, CA** University of California, San Diego, CA*** University of California, Berkeley, CA**** Cornell University, Ithaca, NY***** Peking University, Beijing, China

We use modern methods of quantum chemistry (density functional methods) to investigate the electronic structures, energetics, and spectroscopic characteristics of transition-metal complexes at the active sites of metalloproteins and of related synthetic analogs. These systems include iron-sulfur and iron-oxo complexes and active-site models for manganese, iron, and copper-zinc superoxide dismutases. Many of these complexes lie at the active sites of important metalloproteins, where the complexes are involved in electron transfer and catalysis. In all these systems, 2 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 V. Dillet, Department of Molecular Biology.

We are also involved, through a collaboration with E. Getzoff and M. Thompson, Department of Molecular Biology, in the study of photoactive yellow protein. This protein contains a chromophore that undergoes a light cycle and thus acts as a protein photosensor. Potentially, the absorption and photocycle of photoactive yellow protein can be modulated by designed sites where mutations in amino acid residues cause binding of transition-metal ions. Density functional calculations on the ground and excited states of the chromophore are providing valuable information on electronic and geometric structure. In combination with protein/solvent electrostatics, these methods are beginning also to establish the role of the protein in modulating the energy pathways of the chromophore.

We have calculated electronic structures and optimized geometries for some iron-oxo dimer systems that resemble known synthetic complexes and have begun calculations on active-site structures for the iron-oxo enzymes methane monooxygenase and ribonucleotide reductase.

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. We have examined the role of cluster electronic structure on redox potentials of synthetic iron-sulfur clusters in solution. The solvent was modeled as a continuous dielectric medium. The predicted changes in redox potentials correlated well with experimental trends. This work has been extended to a full self-consistent reaction field method for clusters in protein and solvent environments, and redox potential calculations for 2Fe2S clusters in proteins have been completed.

With M. Knapp, University of California, Berkeley, and D. Hendrickson, University of California, San Diego, we are studying the effect of arylthiolate conformation on the electronic structure and spectra of [Fe₄S₄(SR)₄]^2-,3- complexes. We have begun work, in collaboration with Z. Chen, Peking University, on the electronic structure and reactions of the iron-molybdenum cofactor of the nitrogenase enzyme. This cofactor is the MoFe₇ active site of the iron-molybdenum protein that binds molecular nitrogen and protons and catalyzes the multielectron reduction of molecular nitrogen to 2 ammonia molecules plus molecular hydrogen.

Manganese, iron, and copper-zinc superoxide dismutases are important detoxifying agents for superoxide radical anions, converting these anions to molecular oxygen and hydrogen peroxide. J. Tainer and E. Getzoff, Department of Molecular Biology, are investigating x-ray structures and reaction kinetics of these enzymes. 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, iron, and copper-zinc superoxide dismutases. We also calculated binding of the inhibitor azide to the manganese and iron active-site complexes. We have now extended our model to include larger quantum active-site complexes (beyond the first ligand shell so that important hydrogen bonds are included) and with an electrostatic representation of the complete remaining protein/solvent environment. The entire catalytic cycle of these enzymes is also under investigation.

By a systematic study of transition-metal complexes both in aqueous (or organic) solvents and in more complicated protein environments, we are attaining an integrated analysis of the effects of these different environments on catalytic cycles involving electron and proton transfer.

PUBLICATIONS

Case, D.A., Noodleman, L., Li, J. Modern computational approaches to modeling polynuclear transition metal complexes. In: Metal-Ligand Interactions in Physics, Chemistry, and Biology. Russo, N. (Ed.). Kluwer Academic, Boston, in press. NATO Series.

Konecny, R., Li, J., Fisher, C.L., Dillet, V., Bashford, D., Noodleman, L. CuZn superoxide dismutase geometry optimization, energetics, and redox potential calculations by density functional and electrostatics methods. Inorg. Chem. 38:940, 1999.

Li, J., Fisher, C.L., Konecny, R., Bashford, D., Noodleman, L. Density functional and electrostatic calculations of manganese superoxide dismutase active site complexes in protein environments. Inorg. Chem. 38:929, 1999.

Li, J., Nelson, M.R., Peng, C.Y., Bashford, D., Noodleman, L. Incorporating protein environments in density functional theory: A self-consistent reaction field calculation of redox potentials of [2Fe2S] clusters in ferredoxin and phthalate dioxygenase reductase. J. Phys. Chem. A 102:6311, 1998.

Li, J., Noodleman, L. Electronic structure calculations: Density functional methods for spin polarization, charge transfer, and solvent effects in transition-metal complexes. In: Spectroscopic Methods in Bioinorganic Chemistry. Solomon, E.I., Hodgson, K.O. (Eds.). American Chemical Society, Washington, DC, 1998, p. 179. ACS Symposium Series, Vol. 692.

Li, J., Noodleman, L., Case, D.A. Electronic structure calculations: Density functional methods with applications to transition-metal complexes. In: Inorganic Electronic Structure and Spectroscopy. Vol. 1, Methods. Solomon, E.I., Lever, A.B.P. (Eds.). Wiley, New York, 1999, p. 661.