Electronic structure calculations for the iron complexes at the active sites of iron-oxo and iron-peroxo based enzymes are now making an important contribution to understanding the physical properties and reaction chemistry of these systems. We use high-quality quantum mechanical density functional theory (DFT) methods to describe and analyze active site properties, and link this to an electrostatics-based representation of the longer range protein and solvent environment. Our long term goal to develop a detailed understanding of chemical bonding, reaction energetics and pathways, making a close connection with experimental structural, spectroscopic, and kinetics studies. (1) These DFT methods will be used to calculate accurate geometries, energies, and protonation states for critical intermediates of iron-oxo and iron-peroxo enzymes. The specific enzymes of interest are Class I ribonucleotide reductases (RNRs) methane monooxygenases (MMOs), toluene monoxygenases (Tolos) and Rieske oxygenases. (2) Detailed connections will be made to a number of X-ray, optical and electron/nuclear based spectroscopies. (3) Reaction pathways for these enzymes will be evaluated and compared with experimental kinetics. (4) New theoretical/computational methods will be tested and compared with experiment to further develop the power and analysis capabilities of modem chemical theory. RNRs catalyze the transformation of ribonucleotides to deoxyribonucleotides, the first required and often rate limiting step in DNA synthesis. Consequently, RNR is a drug target in anticancer, antiviral, and antibacterial therapies. MMOs, Tolos, and Rieske oxygenases have great potential for the detoxification of organic pollutants, and are promising as guides to finding environmentally nontoxic methods for the synthesis of valuable chemicals. A better understanding of these enzyme mechanisms should aid experimental work toward these goals. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function A Study Section (MSFA)
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Fabian, Miles
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Scripps Research Institute
La Jolla
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Luber, Sandra; Leung, Sophie; Herrmann, Carmen et al. (2014) EXAFS simulation refinement based on broken-symmetry DFT geometries for the Mn(IV)-Fe(III) center of class I RNR from Chlamydia trachomatis. Dalton Trans 43:576-83
Fu, Li; Xiao, Dequan; Wang, Zhuguang et al. (2013) Chiral sum frequency generation for in situ probing proton exchange in antiparallel ?-sheets at interfaces. J Am Chem Soc 135:3592-8
Xiao, Dequan; Fu, Li; Liu, Jian et al. (2012) Amphiphilic adsorption of human islet amyloid polypeptide aggregates to lipid/aqueous interfaces. J Mol Biol 421:537-47
Rivalta, Ivan; Brudvig, Gary W; Batista, Victor S (2012) Oxomanganese complexes for natural and artificial photosynthesis. Curr Opin Chem Biol 16:11-8
Han, Wen-Ge; Noodleman, Louis (2011) DFT calculations for intermediate and active states of the diiron center with a tryptophan or tyrosine radical in Escherichia coli ribonucleotide reductase. Inorg Chem 50:2302-20
Han, Wen-Ge; Sandala, Gregory M; Giammona, Debra Ann et al. (2011) Mossbauer properties of the diferric cluster and the differential iron(II)-binding affinity of the iron sites in protein R2 of class Ia Escherichia coli ribonucleotide reductase: a DFT/electrostatics study. Dalton Trans 40:11164-75
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Luber, Sandra; Rivalta, Ivan; Umena, Yasufumi et al. (2011) S1-state model of the O2-evolving complex of photosystem II. Biochemistry 50:6308-11
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Han, Wen-Ge; Noodleman, Louis (2010) Quantum cluster size and solvent polarity effects on the geometries and Mössbauer properties of the active site model for ribonucleotide reductase intermediate X: a density functional theory study. Theor Chem Acc 125:305-317

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