DNA Stability and Flexibility: A Thermodynamic Study
Thermodynamic characterization of the molecular forces that dictate and control the sequence-dependent structure and conformational transitions of oligomeric and polymeric nucleic acid molecules. Characterization of the influence of structural modifications (e.g., wobble base pairs, bulge loops, mismatches, etc.), salt, and drug binding on the helix-to-coil and helix-to-helix transitions of DNA molecules. Use of these data to construct comprehensive phase diagrams for DNA polymorphism so that under a given set of solution conditions and ligand binding. DNA secondary structures can be predicted from primary sequence data. Thermodynamic characterization of higher-order DNA structures such as triplexes and tetraplexes. Evaluating the relative binding affinity and specificity of third-strand oligomers to target DNA duplex domains, as a function of base sequence and solution conditions. Such information is required for both the rational design of third-strand oligomers and for the tuning of solution conditions as part of triplex strategies used to modulate biochemical events and to develop diagnostic protocols.
Drug-DNA Interactions: The Thermodynamics of Molecular Recognition
Elucidation of the molecular recognition patterns and characterization of the driving forces that give rise to the binding affinities and sequence/conformational preferences exhibited by DNA binding ligands. Defining the relative contributions of van der Waals contacts, hydrogen bonding, electrostatics, etc. to the binding affinities and specificities of DNA-directed ligands. Correlating specific drug structural features with their DNA binding affinities and specificities. Synergism in DNA drug binding studies. Using the information gained from these studies, one can design rational drug analogues that should exhibit predictably altered binding properties and perhaps desired biological functions.
The Chemistry and Biology of Mutagenic DNA Lesions and Repair Intermediates: The Relationship of DNA Structure and Binding Properties to Biological Function
Characterizations of the impacts of mutagenic lesions and repair intermediates on the structure, stability, and conformation of DNA duplexes. The goal of these studies is to evaluate if the lesion-induced alterations in duplex properties are consistent with or can be used to define biological mechanisms of repair and/or of mutagenesis. A logical extension of these studies, which we currently are pursuing, involves the design and testing of drugs that selectively target DNA sites which contain mutagenic lesions.