Realistic Computational Model for the Catalytic Active Site of Galactose OxidaseAIM analysis of the topology of the electron density for the 6Fe-cluster of FeFe-hydrogenaseCoordination chemical models for interaction of U(VI) ion with PQQ cofactor

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While the topics of our 2008 JBIC [1] and 2006 JACS [2] papers indicate bioinorganic structure/function content, I list these here due to their focus on method development. In these publications we set an example for developing realistic virtual chemistry models for complex metalloenzymes, where outer coordination sphere-effects have been observed by site-directed mutagenesis studies. This work has been carried out in collaboration with the Dooley Group at the Department. We showed that a systematic and careful mapping of the network of weak interactions around the catalytic active site is critical not just to reproduce the experimental structure, but also the spectroscopic signatures and redox potentials. We were able to calculate the two-step redox process in galactose oxidase within 200 mV accuracy without any empirical parameterization.
An important work for our future studies was accomplished with a considerable contribution from a summer undergraduate student, who systematically evaluated the performance of a large list of density functionals and basis sets for both the geometric and electronic structures of a central 4Fe-4S cluster. We published this work in an invited contribution to a special Computational Bioinorganic Chemistry issue of the Journal of Computational Chemistry [3]. We have shown that for achieving 0.03 Å and 0.1 e- or better accuracy in metric parameters and sulfur covalency in the [Fe4S4(SR)4]2- cluster a previously undefined hybrid functional, B(5HF)P86 must be employed with a triple-ζ quality basis set containing both polarization and diffuse functions. This particular 4Fe-4S cluster is generally considered the resting form of clusters in hydrogenase, nitrogenase, ferredoxins, high-potential iron-proteins, SAM radical enzymes, etc. With this work, we also published a fast and user friendly way of generating complex wave functions for broken symmetry calculations of antiferromagnetically coupled states that are essential for correct treatment of iron-sulfur clusters.
As representative examples for providing computational training for visiting undergraduate and graduate students, I wish to highlight a collaborative effort with Prof. Karen McFarlane from Willamette University, and Prof. Jalilehvand’s group at University of Calgary. While both have a strong inorganic spectroscopy tone, my group’s contribution consisted of electronic structural support that actually tied the various measurements together carried out by the collaborator’s group. The students spent few weeks to few months in my group to complete a full electronic structure analysis that was essential in assigning all spectral features. These work allowed us to gain understanding into coordination chemistry of Ru-based anticancer drugs [4] and transition-metal coordination to cysteine residues [5].
With a collaborative project from the Chemical and Biological Engineering Department on campus, we opened up a new research direction for the group that we are actively pursuing [6]. This entails the molecular level description of the chemical toxicity of depleted uranium. The main driving force for this research from our interest is the remarkable coordination chemistry of high valent uranium with completely empty 5d and 4f valence orbitals. This allows for the existence of seven or even higher coordinate complexes with remarkable variability of coordination environment. However, for the aqueous form of U(VI) we found selective and strong coordination affinity to a biologically common [ONO] coordination environment. In the light of the in vivo studies showing that high valent uranium can show toxicity in or even below the currently allowed EPA limits, we are developing a research program to identify additional biological cofactors that may be susceptible to U(VI) coordination and thus can lead us to identification of previously undocumented acute toxicity mechanism.


  1. Rokhsana D., Dooley D.M., Szilagyi R.K.: , "Structure of the Oxidized Active Site of Galactose Oxidase from Realistic In Silico Models ." Journal of the American Chemical Society, 2006, 128(49), 15550-15551
  2. Rokhsana D., Dooley D.M., Szilagyi R.K.: , "Systematic development of computational models for the catalytic site in galactose oxidase: impact of outer-sphere residues on the geometric and electronic structures ." Journal of Biological Inorganic Chemistry, 2008, 13(3), 371-383
  3. Harris T.V., Szilagyi R.K., McFarlane Holman K.L.:, "Electronic Structural Investigations of Ru-containing Compounds and Anticancer Prodrugs." Journal of Biological Inorganic Chemistry, 2009, 14(6), 891-898
  4. Leung B.O., Jalilehvand F., Szilagyi R.K., "Electronic Structure of Transition Metal-Cysteine Complexes from X-ray Absorption Spectroscopy." Journal of Physical Chemistry B, 2008, 112(15), 4770-4778
  5. VanEngelen M.R., Szilagyi R.K., Gerlach R., Lee B.D., Apel W.A., Peyton B.M.:, "Uranium Exerts Acute Toxicity by Binding to Pyrroloquinoline Quinone Cofactor." Environmental Science and Technology, 2011, 45(3), 937-942



Structure, Physical, Inorganic, Computational, Bioinorganic