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

L. Noodleman, D.A. Case, J. Li, R. Konecny, M.E. Stroupe, D.N. Hendrickson,* M.J. Knapp,* J.M. Mouesca,** B. Lamotte,** K. Kustin,*** H. Kuramochi****

* University of California, San Diego, CA
** Centre d'Etudes Nucléaires, Grenoble, France
*** Brandeis University, Waltham, MA
**** Nippon Kayaku Co., Tokyo, Japan

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 related synthetic analogs. These systems include iron-sulfur, iron-oxo, and manganese-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. 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.

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 collaboration with J.M. Mouesca, Centre d'Etudes Nucléaires, Grenoble, France, we have examined the role of cluster electronic structure in 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. This work is being done in collaboration with D. Bashford, Department of Molecular Biology. With M. Knapp and D. Hendrickson at the 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. Work has also begun on the electronic structure and reactions of the iron-molybdenum cofactor of the nitrogenase enzyme. This 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.

In recent collaborative work with H. Kuramochi, Nippon Kayaku Co., Tokyo, we have calculated electronic structures and related physical properties for active-site models of heme compounds I and II, intermediates in heme peroxidase enzymes. These properties include (1) Mossbauer properties of the iron site and oxygen and (2) porphyrin (nitrogen and proton) hyperfine properties for the coupled iron-oxo (ferryl)-porphyrin radical system (compound I). Two close-lying /pibdy/-cation radical electronic states, A_2u and A_1u, were found by using broken symmetry density functional calculations. Overall, the porphyrin radical hyperfine properties are more consistent with an A_2u electronic ground state, as is the magnetic coupling strength observed and the calculated energy separation between A_2u and A_1u. From broken symmetry calculations of the Heisenberg J coupling, a good qualitative analysis of the weak magnetic coupling (both calculated and observed) in the ground electronic state (A_2u) between the porphyrin radical and the ferryl center was derived; the higher lying A_1u excited state displayed much stronger antiferromagnetic coupling (also in agreement with qualitative magnetic orbital overlap arguments). This finding is another example of the value of broken symmetry density functional methods for coupled transition metal--ligand radical systems, as found in our earlier work on metal-semiquinone complexes.

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 redox potentials and pK_a's for the active sites of manganese, iron, and copper-zinc superoxide dismutases. We are extending our model to include an electrostatic representation of the complete protein or solvent environment. The entire catalytic cycle of these enzymes is also under investigation. Our experimental collaborators are J. Tainer, E. Getzoff, and D. McRee of the Department of Molecular Biology.

We have used the self-consistent reaction field method to calculate redox potentials and pK_a's for the transition-metal cations Mn²⁺, Mn³⁺, Fe²⁺, and Fe³⁺ in aqueous solution. These simpler systems provide a starting point for analyzing redox and protonation-deprotonation events in more complex systems, including manganese and iron superoxide dismutases.

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

Kuramochi, H., Noodleman, L., Case, D.A. Density functional study on the electronic structures of model peroxidase compounds I and II. J. Am. Chem. Soc. 119:11442, 1997.

Li, J., Beroza, P., Noodleman, L., Case, D.A. Quantum mechanical modeling of active sites in metalloproteins: Electrostatic coupling to the protein/solvent environment. In: NATO Advanced Study Institute Molecular Modeling and Dynamics of Biological Molecules Containing Metal Ions. Banci L., Comba, P. (Eds.). Kluwer, Boston, 1997, p. 279.

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, in press.

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

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, in press.