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Drug-DNA interactions. DNA polymorphism. macroscopic and microscopic characterizations of inter- and intramolecular forces. biothermodynamics. DNA lesions and mechanisms of mutagenesis and repair. ligand-biopolymer recognition. rational drug design. DNA-based diagnostics and therapeuticsDNA 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. Selected PublicationsMinetti CA, Remeta DP, Breslauer KJ. (2008) A continuous hyperchromicity assay to characterize the kinetics and thermodynamics of DNA lesion recognition and base excision. Lee BJ, Barch M, Castner EW Jr, Völker J, Breslauer KJ. (2007) Structure and dynamics in DNA looped domains: CAG triplet repeat sequence dynamics probed by 2-aminopurine fluorescence. Biochemistry. 46(38):10756-66. Volker J, Klump HH, Breslauer KJ. (2007) DNA metastability and biological regulation: Conformational dynamics of metastable Omega-DNA bulge loops. J Am Chem Soc. 129(16):5272-5280. Plum GE, Breslauer DN, Breslauer KJ. (2007) High resolution protein-DNA binding energy landscapes via a novel high throughput method. Biopolymers. 85(5-6):vii-viii. Volker J, Klump HH, Breslauer KJ. (2007) The energetics of i-DNA tetraplex structures formed intermolecularly by d(TC(5)) and intramolecularly by d[(C(5)T(3))(3)C(5)]. Biopolymers. 86(2):136-147 Breslauer KJ. (2007) Julian Sturtevant: scientific giant, warm humanist, social activist, nature lover, gentle teacher, kind friend. Biophys Chem. 126(1-3):9-10. Privalov PL, Dragan AI, Crane-Robinson C, Breslauer KJ, Remeta DP, Minetti CA. (2007) What drives proteins into the major or minor grooves of DNA? J Mol Biol. 365(1):1-9. Braunlin. W.H.. Giri. I.. Beadling. L. and Breslauer. K.J. (2004) Conformational screening of oligonucleotides by variable-temperature HPLC: Dissecting the duplex-hairpin-coil equilibria of d(CGCGAATTCGCG). Biopolymers 74: 221-231. Minetti. C.A.S.A.. Remeta. D.P.. Miller. H.. Gelfand. C.. Plum. G.E.. Grollman. A.P. and Breslauer. K.J. (2003) The thermodynamics of template-directed DNA synthesis: base insertion and extension enthalpies. Proc. Natl. Acad. Sci. USA 100: 14719-14724. Minetti. C.A.S.A . Remeta. D.P.. Zharkov. D.. Plum. G.E.. Johnson. F.. Grollman. A.P. and Breslauer. K.J.(2003). Energetics of lesion recognition by a DNA repair protein: Thermodynamic characterization of formamidopyrimidine-glycosylase (Fpg) interactionswith damaged DNA duplexes. J. Molec. Biol. 328:1047-1060. Völker. J.. Makube. N.. Plum. G.E.. Klump. H.H. and Breslauer. K.J. (2002). Conformational energetics of stable and metastable states formed by DNA triplet repeat oligonucleotides: Implications for triplet expansion diseases. Proc. Natl. Acad. Sci. USA 99:14700-14705. Plum G.E.and Breslauer. K.J. (2002). Fluorescence energy transfer monitored competitive equilibria of nucleic acids: Applications in thermodynamics and screening. Biopolymers: Nucleic Acid Sciences 61:214-223. Kaletunç G.and Breslauer. K.J. (2002). "Calorimetry of pre-and postextruded cereal flours. " in Characterization of Cereals and Flours: properties. Analysis. and Applications. Marcel Dekker. Inc.. NY. NY pp. 1-36. Völker. J.. Klump. H. and Breslauer. K.J. (2001). Communication between non-contacting macromolecules. Proc. Natl. Acad. Sci. USA 98:7694-7699. Völker. J.. Klump. H.. Manning. G.S and Breslauer. K.J. (2001) Counterion association with native and denatured DNA: an experimental approach.J. Mol. Biol. 310:1011-1025. Pilch. D.S.. Dunham. S.U.. Jamieson. E.R.. Lippard. S.J.. and Breslauer. K.J. (2000). DNA sequence context modulates the impact of a cisplatin 1,2-d(GpG) intrastrand cross-link on the conformational and thermodynamic properties of duplex DNA. J. Mol. Biol. 296:803-812. Chalikian. T.V. and Breslauer. K.J. (2000). Volumetric properties of nucleic acids. Biopolymers: Nucl. Acid Sciences 48:264-280. Pilch. D.S.. Poklar. N.. Baird. E.E.. Dervan. P.B.. and Breslauer. K.J. (1999). The thermodynamics of polyamide-DNA recognition: hairpin polyamide binding in the minor groove of duplex DNA Biochemistry 38:2143-2151. Völker. J.. Blake. R.D.. Delcourt. S.G.. and Breslauer. K.J. (1999). High resolution calorimetric and optical melting profiles of DNA plasmids: resolving contributions from intrinsic melting domains and specifically designed inserts. " Biopolymers 50:303-318. Gelfand. C.A.. Plum. G.E.. Mielewczyk. S.. Remeta. D.P.. and Breslauer. K.J. (1999). A quantitative method for evaluating the stabilities of nucleic acid complexes. Proc. Natl. Acad. Sci. 96:6113-6118. Chalikian. T.V.. Völker. J.. Plum. G.E.. and Breslauer. K.J. (1999). A more unified picture for the thermodynamics of nucleic acid duplex melting: a characterization by calorimetric and volumetric techniques. " Proc. Natl. Acad. Sci. 96:7853-7858. Chalikian. T.V.. Völker. J.. Srinivasan. A.R.. Olson. W.K.. and Breslauer. K.J. (1999).The hydration of nucleic acid duplexes as assessed by a combination of volumetric and structural techniques. Biopolymers 50:459-471.
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