Our long-term goal is to develop an understanding of the molecular forces that dictate and control the affinity and specificity of drug binding to DNA. Such a molecular understanding of drug-DNA interactions is a prerequisite for the development of a rational basis for drug design. Our approach is to determine complete thermodynamic binding profiles for the complexation of several antitumor and antiviral drugs to various DNA host duplexes. Specifically, spectroscopy and batch calorimetry will be employed to characterize thermodynamically the binding event as a function of the structure of the drug and the sequence of both oligomeric and polymeric host DNA's. These thermodynamic binding profiles for each drug will allow us to: define the nature of the forces that drive complexation and predict the temperature-dependent stability of the complex; determine the thermodynamic origin of sequence binding preferences; define the thermodynamic basis for cooperative binding; evaluate the role of specific structural features of the drug by comparing the binding data on a series of drug analogues; correlate the thermodynamic data with the mode of binding and the molecular picture of the complex; resolve drug-induced conformational changes from local, specific drug-DNA interactions by comparing binding data on corresponding oligomeric and polymeric DNA hosts; evaluate the thermodynamic basis for drug synergism by comparing binding data for a drug in the presence and absence of other drugs. Differential scanning calorimetry will be used to detect, monitor, and thermodynamically characterize the influence of drug binding on the melting behavior of the host duplex. In particular, the size of the cooperative melting unit for each host duplex will be determined in the presence and absence of each drug. This parameter will provide a measure of the influence of drug binding and base sequence on the ability of a polymer chain to propagate molecular distortions -- a property which undoubtedly is of great importance in numerous biological processes. Calorimetry represents the only experimental method by which the relevant thermodynamic data can be obtained in a direct and model-independent manner. In conjunction with standard spectroscopic techniques, this proposal is designed to exploit the unique powers of batch and differential scanning calorimetry to obtain complete thermodynamic and extra-thermodynamic profiles of the solution properties of drug binding and the resultant drug-DNA complexes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034469-04
Application #
3285523
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1985-01-01
Project End
1989-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Rutgers University
Department
Type
Schools of Arts and Sciences
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Völker, Jens; Plum, G Eric; Gindikin, Vera et al. (2014) Impact of bulge loop size on DNA triplet repeat domains: Implications for DNA repair and expansion. Biopolymers 101:1-12
Li, Mengxia; Völker, Jens; Breslauer, Kenneth J et al. (2014) APE1 incision activity at abasic sites in tandem repeat sequences. J Mol Biol 426:2183-98
Braunlin, William; Völker, Jens; Plum, G Eric et al. (2013) DNA meter: Energy tunable, quantitative hybridization assay. Biopolymers 99:408-17
Völker, Jens; Gindikin, Vera; Klump, Horst H et al. (2012) Energy landscapes of dynamic ensembles of rolling triplet repeat bulge loops: implications for DNA expansion associated with disease states. J Am Chem Soc 134:6033-44
Völker, Jens; Plum, G Eric; Klump, Horst H et al. (2010) Energetic coupling between clustered lesions modulated by intervening triplet repeat bulge loops: allosteric implications for DNA repair and triplet repeat expansion. Biopolymers 93:355-69
Minetti, Conceição A S A; Remeta, David P; Johnson, Francis et al. (2010) Impact of alpha-hydroxy-propanodeoxyguanine adducts on DNA duplex energetics: opposite base modulation and implications for mutagenicity and genotoxicity. Biopolymers 93:370-82
Minetti, Conceicao A S A; Remeta, David P; Dickstein, Rian et al. (2010) Energetic signatures of single base bulges: thermodynamic consequences and biological implications. Nucleic Acids Res 38:97-116
Völker, Jens; Plum, G Eric; Klump, Horst H et al. (2010) Energy crosstalk between DNA lesions: implications for allosteric coupling of DNA repair and triplet repeat expansion pathways. J Am Chem Soc 132:4095-7
Völker, Jens; Plum, G Eric; Klump, Horst H et al. (2009) DNA repair and DNA triplet repeat expansion: the impact of abasic lesions on triplet repeat DNA energetics. J Am Chem Soc 131:9354-60
Minetti, Conceicao A S A; Remeta, David P; Breslauer, Kenneth J (2008) A continuous hyperchromicity assay to characterize the kinetics and thermodynamics of DNA lesion recognition and base excision. Proc Natl Acad Sci U S A 105:70-5

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