Thermodynamic characterization of daunomycin-DNA interactions: Comparison of complete binding profiles for a series of DNA host duplexes

• Published in: Biochemistry (Easton) 1993-05, Vol.32 (19), p.5064-5073
• Main Authors: Remeta, David P, Mudd, Courtney P, Berger, Robert L, Breslauer, Kenneth J
• Format: Article
• Language: English
• Subjects: Base Composition; Binding Sites; Biological and medical sciences; Calorimetry, Differential Scanning; Daunorubicin - metabolism; DNA - chemistry; DNA - metabolism; General pharmacology; Medical sciences; Molecular Structure; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Polydeoxyribonucleotides - metabolism; Spectrophotometry; Temperature; Thermodynamics
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi00070a014

Using a combination of spectroscopic and calorimetric techniques, we have determined complete thermodynamic binding profiles (delta G degree, delta H degree, and delta S degree) for the complexation of daunomycin to a series of 10 polymeric DNA duplexes. We find the resulting drug binding data to be sensitive to the base composition and sequence of the host duplex, with the binding free energies ranging from -7.5 to -10.8 kcal/mol of bound drug and the binding enthalpies ranging from +4.11 to -10.76 kcal/mol of bound drug at 25 degrees C. The smaller range in the free energy term reflects the impact of large enthalpy-entropy compensations. We observe that the three synthetic duplexes which exhibit the highest daunomycin binding affinities all contain GC (or IC) base pairs as part of alternating purine/pyrimidine sequence motifs, with these high binding affinities being strongly enthalpy driven at 25 degrees C. Specific comparisons between the binding profiles for daunomycin complexation with select pairs of host duplexes lead to the following observations: (1) The presence or absence of a major-groove methyl group does not alter daunomycin binding thermodynamics. (2) The presence or absence of a minor-groove amino group does alter daunomycin binding thermodynamics. (3) Duplexes with different base compositions but identical minor-groove functionality exhibit similar daunomycin binding thermodynamics. (4) Homopolymeric duplexes composed of either AT or AU base pairs, but not GC base pairs, exhibit large enthalpy-entropy compensations in their daunomycin binding profiles. We propose interpretations of these and other features of our thermodynamic data in terms of specific daunomycin-DNA interactions deduced from available structural data.