Professor Thomas R. KrughNMR Structural Characterization of Nucleic Acids |
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Professor of Chemistry Ph.D. '69 Pennsylvania State University
Department of Chemistry |
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Krugh Group | Chemistry | Faculty | Graduate | Undergraduate | UR
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Summary of Research Interest |
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We are interested in the three-dimensional structure, dynamics, and
thermodynamics of DNA and RNA oligomers. DNA oligomers contain chemical
modifications that are important in the area of mutagenesis.
Two-dimensional NMR experiments are used to assign nucleic acid
resonances and to measure intermolecular distances. These distances are
input as distance restraints in energy minimization and molecular
dynamics calculations to obtain detailed three-dimensional structures.
N-2-Aminofluorene, a model carcinogen used extensively in carcinogenesis
and mutation studies, binds covalently to the C8 position of guanine.
The structure of an aminofluorene-DNA oligomer has been reported (AF Abstract). Actually, we found two
structures, as the aminofluorene-modified oligomer duplex exists as two
conformations in equilibrium, with approximately equal populations. This
equilibrium is illustrated in the schematic diagram and in the chemical structures shown on another page.
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The aminofluorene, AF, moiety is external to the duplex in one conformer
(labeled the external-AF conformer), while in the other conformer the AF
moiety is stacked within the helix, with disruption of base pairing. The
Watson-Crick base pairing observed in the external-AF structure would
allow faithful replication of the AF-modified strand, while the
disruption of base pairing in the inserted-AF structure provides a
visualization of a premutagenic conformer.
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Other studies involve benzo[a]pyrene adducts and N-acetyl-2-aminofluorene (AAF),
modified DNA oligomers. In collaboration with Professor Lawrence
(Biophysics), we are investigating the structure of thymine dimers
incorporated into DNA oligomers. These pyrimidine(6-4) pyrimidone lesions
are observed as a result of excess exposure to UV radiation and are
thought to be important in skin cancer.
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The structure of an RNA
hairpin also has been recently reported (Abstract) in a project done in
collaboration with Professors Turner
(Rochester) and Serra (Allegheny College).
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Selected Recent Publications |
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Fountain, M. A., Serra, M. J., Krugh, T. K., and Turner, D. H.,
"Structural Features of a Six-Nucleotide RNA Hairpin Loop Found in
Ribosomal RNA," Biochemistry (1996), 35, 6539-6548. Abstract
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Fountain, M. A. and Krugh, T. R., "Structural Characterization of a
(+)-trans-anti-Benzo[a]pyrene-DNA Adduct Using NMR,
Restrained Energy Minimization and Molecular Dynamics,"
Biochemistry (1995), 34, 3152-3161. Abstract
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Krugh, T. R., "Drug-DNA Interactions," Current Opinions in
Structural Biology (1994), 4, 351-364. Abstract
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Eckel, L. M.; Krugh, T. R., "2-Aminofluorene Modified DNA Oligomer
Duplex Exists in Two Interchangeable Conformations," Nature,
Structural Biology (1994), 1, 89-94. Abstract
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Eckel, L. M. and Krugh, T. R., "Structural Characterization of Two
Interchangeable Conformations of a N-2-Aminofluorene-Modified DNA
Oligomer by NMR and Energy Minimization," Biochemistry (1994),
33, 13611-13624. Abstract
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O'Handley, S. F., Sanford, D. G., Xu, R.; Lester, C. C., Hingerty, B. E.,
Broyde, S.; Krugh, T. R., "Structural Characterization of an
N-Acetyl-2-aminofluorene (AAF) Modified DNA Oligomer by NMR, Energy
Minimization, and Molecular Dynamics," Biochemistry (1993),
32, 2481-2497. Abstract
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