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Integrative Structural and Computational Biology

Louis Noodleman, PhD

Professor Emeritus
Department of Integrative Structural and Computational Biology
California Campus
Laboratory Website
(858) 784-2840

Scripps Research Joint Appointments

Faculty, Graduate Program

Research Focus

Electronic Structure and Reactions of Iron-Sulfur Electron Transfer Proteins and Redox Enzymes, and for Iron-Oxo Enzymes

We use modern methods of quantum chemistry (density functional methods) and protein electrostatics to investigate electronic structures, spectroscopy and the reaction pathways for the active sites of redox metalloproteins. (1) Iron-sulfur proteins are electron transfer agents in the electron transport chains of respiration, photosynthesis, and for metabolic conversions. (2) The enzyme nitrogenase is a complicated multielectron redox catalyst for the conversion of molecular nitrogen to ammonia, forming a primary building block for making amino and nucleic acids. (3)  The iron-oxo dimer enzymes methane monooxygenase (MMO) and ribonucleotide reductase (RNR) use two electron redox and oxygen activation chemistry. MMO hydroxylates hydrocarbons while RNR produces a tyrosine radical which by a long range hole propagation and H abstraction generates deoxyribonucleotides from ribonucleotides, the first step in DNA synthesis. (4) Cytochrome c oxidases (CcOs) are redox driven proton pumps in the membranes of mitochondria and many aerobic bacteria. CcOs are the
terminal oxidases (Complex IV)  of the electron transport chain in mitochondria and aerobic bacteria, and drive ATP synthesis by producing the required
electrochemical potential gradient (proton motive force) across the membrane, in conjunction with  membrane Complexes I and III.

These are chemically difficult and biologically important reactions. Common themes include the coupling between electron and proton transfer, the modulation of redox potentials by the active site cluster and the protein and solvent environment, and the activation of small molecule substrates, including molecular nitrogen or oxygen.


Ph.D., Materials Science, Massachusetts Institute of Technology, 1975

Awards & Professional Activities

Editorial Advisory Board, Journal of Biological Inorganic Chemistry, 2000 - 2002 (Springer), Editorial Board, Interdisciplinary Sciences: Computational Life Sciences, 2008-2013 (Springer)

Selected References

Noodleman, L., Lovell, T., Han, W.-G., Li, J., Himo, F. Quantum Chemical Studies of Intermediates and Reaction Pathways in Selected Enzymes and Catalytic Synthetic Systems. Chem. Rev. 104, 459-508, 2004.

Himo, F., Lovell, T.A., Hilgraf, R., Rostovstev, V.V., Noodleman, L., Sharpless, K.B., Fokin, V.V.  Copper(I) -Catalyzed Synthesis of Azoles.
DFT Study Predicts Unprecented Reactivity and Intermediates. J. Am. Chem. Soc. 127, 210-216, 2005.

Noodleman, L., Han, W.-G. Structure, Redox, pKa, Spin. A Golden Tetrad for Understanding Metalloenzyme Energetics and Reaction Pathways. J. Biol. Inorg. Chem. 11, 674-694, 2006.

Toutchkine, A., Han, W.-G., Ullmann, M., Liu, T., Bashford, D., Noodleman, L., Hahn, K.M. Experimental and DFT studies: novel structural modifications greatly enhance the solvent sensitivity of live cell imaging dyes. J. Phys. Chem. A 111:10849, 2007.

Lukoyanov, D., Pelmenschikov, V., Maeser, N., Laryukhin, M., Yang, T.C., Noodleman, L., Dean, D.R., Case, D.A., Seefeldt, L.C., Hoffman, B.M. Testing if the interstitial atom, X, of the nitrogenase molybdenum-iron cofactor is N or C: ENDOR, ESEEM, and DFT studies of the S = 3/2 resting state in multiple environments. Inorg. Chem. 46:11437, 2007.

Fee, J.A., Case, D.A., Noodleman, L. Toward a chemical mechanism of proton pumping by the B-type cytochrome c oxidases: application of density functional theory to cytochrome ba3 of Thermus thermophilus. J. Am. Chem. Soc. 130:15002, 2008.

Pelmenschikov, V., Case, D.A., Noodleman, L. Ligand-bound S = 1/2 FeMo-cofactor of nitrogenase: hyperfine interaction analysis and implication for the central ligand X identity. Inorg. Chem. 47:6162, 2008.

Han, W.-G., Noodleman, L. Structural model studies for the high-valent intermediate Q of methane monooxygenase from broken-symmetry density functional calculations. Inorganica Chim. Acta 361:973, 2008.

Han, W.-G., Noodleman, L. Structural Model Studies for the Peroxo Intermediate P and Reaction Pathway from P->Q of Methane Monooxygenase using Broken Symmetry Density Functional Calculations. Inorg. Chem. 47, 2975-2986, 2008.

Noodleman, L., Pique, M.E., Roberts, V.A. Properties and functions of iron-sulfur clusters. In: Wiley Encyclopedia of Chemical Biology. Begley, T.P. (Ed.). Wiley Interscience, New York, electronic version doi:10.1002/9780470048672.wecb706, 2008.

Noodleman, L., Case, D.A. Broken Symmetry States of Iron Sulfur Clusters, in "Computational Inorganic and Bioinorganic Chemistry", edited by E.I.  Solomon, R.A. Scott, and R.B. King, Encyclopedia of Inorganic Chemistry Book Series, John Wiley and Sons, Ltd., Chichester, UK, pp.213-228, 2009.

Han, W.-G., Noodleman, L DFT calculations of the comparative energetics and ENDOR/Mossbauer properties for two protonation states of the iron dimer cluster of ribonucleotide reductase intermediate X. Dalton Transactions 6045-6057, 2009

Hopmann, K.H., Ghosh, A., Noodleman, L. Density Functional Theory Calculations on Mossbauer Parameters of Nonheme Iron Nitrosyls. Inorg. Chem. 48, 9155-9165, 2009.

Han, W.-G., Noodleman, L. Quantum Cluster size and solvent polarity effects on the geometries and Mossbauer properties of the active site model for ribonucleotide reductase intermediate X: a density functional theory study. Theor. Chem. Accounts 125, 305-317, 2010.

Han, W.-G., Giammona, D.A., Bashford, D., Noodleman, L. Density Functional Theory Analysis of Structure, Energetics, and Spectroscopy for the MnFe active Site of Chlamydia trachomatis Ribonucleotide Reductase in Four Oxidation States. Inorg. Chem. 49, 7266-7281, 2010.

Hopmann, K.H., Noodleman, L., Ghosh, A. Spin Coupling in Roussin's Red and Black Salts. Chem. Eur. J. 16, 10397-10408, 2010.

Sandala, G.M., Noodleman, L. Modeling the MoFe Nitrogenase System with Broken Symmetry Density Functional Theory, in Nitrogen Fixation:  Methods and Protocols, edited by M.W. Ribbe, Humana Press (Springer Science+Business Media, LLC), New York,
NY, in press.

Han, W.-G., Noodleman, L. DFT Calculations for Intermediate and Active States of the Diiron Center with a Tryptophan or Tyrosine Radical in Escherichia coli Robonucleotide Reductase. Inorg. Chem. 50, 2302-2320, 2011

Bhave, D., Han, W.-G., Pazicni, S., Penner-Hahn, J., Carroll, K., Noodleman, L. Geometric and Electrostatic Study of the [4Fe-4S] Cluster of Adenosine-5'-Phosphosulfate Reductase from Broken Symmetry Density Functional Calcultions and Extended X-ray Absorption Fine Structure Spectroscopy. Inorg. Chem. 50, 6610-6625, 2011.

Han,W.-G., Sandala, G.M., Giammona, D.A., Bashford, D., Noodleman, L. Mossbauer Propoerties 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 Transactions 40, 1-12, 2011.

Sandala, G.M., Hopmann, K.H., Ghosh, A., Noodleman, L. Calibration of DFT Functionals for the Prediction of 57Fe Mossbauer Spectral Parameters in Iron-Nitrosyl and Iron-Sulfur Complexes. J. Chem. Theory Comput., in press, 2011.

Luber, S., Leung, S., Herrmann, C., Han Du, W.-G., Noodleman, L., Batista, V.S.  EXAFS simulation refinement based on broken-symmetry DFT geometries for the Mn(IV)-Fe(III) center of class I RNR from Chlamydia trachomatis.  Dalton Transactions 43, 576-583, 2013.

Han Du, W.-G., Noodleman, L., Density Functional Study for the Bridged Dinuclear Center Based on a High-Resolution X-ray Crystal Structure of ba(3) Cytochrome c oxidase from Thermus Thermophilus. Inorg. Chem. 52, 14072-14088, 2013.

Noodleman, L., Han Du, W.-G, Fee, J.A., Gotz, A.W., Walker, R.C. Linking Chemical Electron-Proton Transfer to Proton Pumping in cytochrome c Oxidase: Broken-Symmetry DFT Exploration of Intermediates along the Catalytic Reaction Pathway of the Iron-Copper Dinuclear Complex.  Inorg. Chem. 53, 6458-6472, 2014.

Blachly, P.G., Sandala, G.M., Giammona D.A., Liu, T., Bashford, D., McCammon, J.A., Noodleman, L.  Use of Broken-Symmetry Density Functional Theory to Characterize the IspH Oxidized State:  Implications for IspH Mechanism and Inhibition.  J. Chem. Theory Comput. 10, 3871-3884, 2014.


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