Because of its structure and variable base composition, DNA is not an isotropic material. The overall objective of this work is to understand how the local properties of DNA depend on its sequence. DNA in cells is folded into higher order structures, whose energetics depend on the local shape and resistance to deformation. Most of the human genome does not code for proteins, but may contain signals for folding and regulatory regions if we could read them. Understanding the variation of DNA flexibility and curvature with sequence should help provide the needed decoding algorithm. The method of DNA cyclization kinetics, using specially designed cyclization constructs in a high-throughput mode, will be used to characterize the properties of specific sequence elements, alone and in complex with ligands such as proteins and sequence- specific polyamides. The sequence-dependence of the dynamic properties of DNA deformation is also poorly understood at present, a deficit that the proposed work will address through the kinetic and dynamic properties of protein and polyamide complexes, with a special focus on cases in which the DNA is bent.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM021966-28
Application #
6423666
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Lewis, Catherine D
Project Start
1978-02-01
Project End
2006-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
28
Fiscal Year
2002
Total Cost
$476,190
Indirect Cost
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Huang, Shar-yin N; Crothers, Donald M (2008) The role of nucleotide cofactor binding in cooperativity and specificity of MutS recognition. J Mol Biol 384:31-47
Zhang, Yongli; McEwen, Abbye E; Crothers, Donald M et al. (2006) Statistical-mechanical theory of DNA looping. Biophys J 90:1903-12
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Sugimura, Sawako; Crothers, Donald M (2006) Stepwise binding and bending of DNA by Escherichia coli integration host factor. Proc Natl Acad Sci U S A 103:18510-4
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Zhang, Yongli; Xi, Zhiqun; Hegde, Rashmi S et al. (2004) Predicting indirect readout effects in protein-DNA interactions. Proc Natl Acad Sci U S A 101:8337-41
Bartoschek, Stefan; Buurman, Gerrit; Geierstanger, Bernhard H et al. (2003) Measurement and ab initio calculation of CSA/dipole-dipole cross-correlated relaxation provide insight into the mechanism of a H2-forming dehydrogenase. J Am Chem Soc 125:13308-9
Barbic, Andrej; Zimmer, Daniel P; Crothers, Donald M (2003) Structural origins of adenine-tract bending. Proc Natl Acad Sci U S A 100:2369-73
Zhang, Yongli; Crothers, Donald M (2003) Statistical mechanics of sequence-dependent circular DNA and its application for DNA cyclization. Biophys J 84:136-53

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