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Molecular Biology
Quantum Bioinorganic Chemistry
and Photochemistry
L. Noodleman, D.A. Case, W.-G.
Han, T. Lovell,* T. Liu,** M.J. Thompson,*** R.A. Torres
* AstraZeneca R&D, Mölndal,
Sweden
** Montana State University, Bozeman, Montana
*** Boston University, Boston, Massachusetts
We use
a combination of modern quantum chemistry (density functional methods) and classical electrostatics
to describe the energetics, reaction pathways, and spectroscopic properties of enzymes and to
analyze systems with novel catalytic, photochemical, or photophysical properties.
Our major efforts are still directed toward
understanding the intermediates and transition states for reactions of redox-active metalloenzymes.
The iron-molybdenum cofactor center of nitrogenase catalyzes the multielectron reduction of
molecular nitrogen to ammonia and molecular hydrogen. This complex cofactor contains a MoFe7S9X
prismane active site. The ultra-high-resolution x-ray structure (1.16 Å) and our density
functional analysis of redox potentials, structures, and Mössbauer isomer shifts indicate
that the stable endogenous central ligand X (Fig. 1) most likely is nitride (N3–).
We also predicted the resting oxidation and protonation state on the basis of these calculations
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| Fig. 1. The FeMoco of nitrogenase with an unknown ligand (X) sitting
in the center. |
Class I ribonucleotide reductases are
aerobic enzymes that catalyze the reduction of ribonucleotides to deoxyribonucleotides, providing
the required building blocks for DNA replication and repair. These ribonucleotide-to-deoxyribonucleotide
reactions occur by a long-range radical (or proton-coupled electron transfer) propagation mechanism
initiated by a fairly stable tyrosine radical, “the pilot light.” When this pilot light
goes out, the tyrosine radical is regenerated by a high-oxidation-state Fe(III)-Fe(IV)-oxo
enzyme intermediate, called intermediate X. We are using density functional and electrostatics
calculations in combination with analysis of Mössbauer and electron nuclear double resonance
spectroscopies to search for a proper structural and electronic model for intermediate X (Fig.
2).
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| Fig. 2. Selected core structures of our initial tested models
for ribonucleotide reductase intermediate state X. |
In
a collaboration with F. Neese, W. Lubitz, and S. Sinnecker, Max-Planck-Institut für Strahlenchemie,
Mülheim an der Ruhr, Germany, we calculated electron paramagnetic resonance and electron
nuclear double resonance parameters for a well-defined exchange coupled Mn(III)Mn(IV)-di-μ-oxo
complex for which careful studies with these experimental spectroscopies have been done. These
methods will be useful for spin-coupled manganese complexes and related enzymes (e.g., manganese
catalases).
In
studies with E. Getzoff and M.J. Thompson, Department of Molecular Biology, and D. Bashford, St.
Jude Children’s Research Hospital, Memphis, Tennessee, we are examining the basis for the
spectral tuning of the chromophore at the active site of photoactive yellow protein as an example
of a light-activated signal-transducing protein. This research combines the expertise of our
different groups in x-ray structure and spectroscopy, electrostatics, and quantum chemistry
for ground and excited states.
In collaboration with K. Hahn, A. Toutchkine,
and D. Gremiachinsky, Department of Cell Biology; F. Himo, Royal Institute of Technology, Stockholm,
Sweden; and M. Ullmann, Universität Bayreuth, Bayreuth, Germany, we examined the optical
properties of solvent-dependent fluorescent dyes as prototypes for fluorescent tags that can
act as reporters of protein conformational change due to ligand binding. These detailed calculations
will be used to deduce general principles to improve design strategies for stable and optically
useful dyes.
Also, with Dr. Bashford’s group,
we are studying reaction pathways for the catalytic dephosphorylation of a tyrosine side chain
by a low molecular weight protein tyrosine phosphatase. The reaction occurs in 2 distinct steps:
first, formation and then hydrolysis of a phosphocysteine intermediate. The related reaction
pathways have different proton-transfer characteristics.
In collaboration with T.C. Bruice, University
of California, Santa Barbara, we used density functional theory to study the magnesium-catalyzed
hydrolysis of the phosphodiester bond in the hammerhead ribozyme in order to generate a 2¢,3¢
cyclic phosphate ester with elimination of the adjacent 5¢
alkoxy group. The reaction pathway shows an associative mechanism with 2 structurally distinct
transition states (Fig. 3) and 1 intermediate, but all are close in energy. Two different proton
transfers within the inner magnesium ion hydration sphere are involved in the reaction.
 |
| Fig. 3. The quantum mechanically optimized structure corresponding
to the first transition state (TS1) in our examination of magnesium-mediated phosphodiester
hydrolysis in the hammerhead ribozyme. Atom names reflect RNA nomenclature. |
We are continuing our collaboration with
K.B. Sharpless, V. Fokin, R. Hilgraf, and V. Rostovtsev, Department of Chemistry, on the catalytic
mechanisms used by transition metal ions in click chemistry, in which metal centers catalyze ring
formation from multiply bonded precursors. Our current focus is copper(I) reactions, because
copper(I) in water shows great versatility in ligating organic azides and alkynes to form 5-membered
heterocycles (triazoles) with wide molecular diversity.
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Publications
Han, W.-G., Liu, T., Himo, F., Toutchkine,
A., Bashford, D., Hahn, K., Noodleman, L. A theoretical study
of the UV/visible absorption and emission solvatochromic properties of solvent-sensitive dyes.
Chemphyschem 4:1084, 2003.
Han, W.-G., Lovell, T., Liu, T.,
Noodleman, L. Density functional study of a μ-1,1-carboxylate
bridged Fe(III)-O-Fe(IV) model complex, 2: comparison with ribonucleotide reductase intermediate
X. Inorg. Chem. 43:613, 2004.
Himo, F., Demko, Z.P., Noodleman,
L. Density functional study of the intramolecular [2 + 3]
cycloaddition of azide to nitriles. J. Org. Chem. 68:9076, 2003.
Liu, T., Han, W.-G., Himo, F., Ullmann,
G.M., Bashford, D., Toutchkine, A., Hahn, K., Noodleman, L.
Density functional vertical self-consistent reaction field theory for solvatochromism studies
of solvent-sensitive dyes. J. Phys. Chem. A 108:3545, 2004.
Liu, T., Lovell, T., Han, W.-G.,
Noodleman, L. DFT calculations of isomer shifts and quadrupole
splitting parameters in synthetic iron-oxo complexes: applications to methane monooxygenase
and ribonucleotide reductase. Inorg. Chem. 42:5244, 2003.
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,
2004.
Noodleman, L., Lovell, T., Han,
W.-G., Liu, T., Torres, R.A., Himo, F. Density functional
theory. In: Fundamentals: Physical Methods, Theoretical Analysis, and Case Studies.
Lever, A.B.P. (Ed.). Philadelphia, Elsevier, 2003, p. 491. Comprehensive Coordination Chemistry
II: From Biology to Nanotechnology, Vol. 2. McCleverty, J.A., Meyer, T.J. (Eds.).
Sinnecker, S., Neese, F., Noodleman,
L., Lubitz, W. Calculating the electron paramagnetic resonance
parameters of exchange coupled transition metal complexes using broken symmetry density functional
theory: application to a MnIII/MnIV model compound. J. Am. Chem. Soc. 126:2613, 2004.
Torres, R.A., Himo, F., Bruice,
T.C., Noodleman, L., Lovell, T. Theoretical examination
of Mg2+-mediated hydrolysis of a phosphodiester linkage as proposed for the hammerhead
ribozyme. J. Am. Chem. Soc. 125:9861, 2003.
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