title: DNA sequence-specific reading by echinomycin: role of hydrogen bonding and stacking interactions.
abstract: The binding of echinomycin to DNA hexamers of the form GpApXpZpTpC, where the central XpZ step can be CpG, TpA, GpC, or ApT, has been studied by molecular modeling and molecular mechanics techniques. Interaction energies have also been calculated for the complexation of echinomycin with sequences containing the preferred central CpG step and different flanking base pairs. Besides, two more sets of sequences incorporating either 2,6-diaminopurine (DAP) or hypoxanthine in place of adenine or guanine, respectively, have been examined. The aim of this work was to evaluate the relative importance of hydrogen-bonding and stacking interactions in the association of echinomycin with DNA and further rationalize the experimental evidence. The results of these calculations are in consonance with available data from footprinting experiments and appear to support our previous hypothesis that, in addition to the crucial intermolecular hydrogen bonds in the central region, the stacking interactions involving the quinoxaline-2-carboxamide chromophores of the drug and the DNA base pairs play an important role in modulating the binding specificity of this bisintercalating antitumor antibiotic. This is most clearly seen when sequences with similar minor-groove environments are compared (e.g. CpI vs TpA or CpG vs TpDAP). The dipole moment of N-methylquinoxaline-2-carboxamide has been measured (mu = 4.15 +/- 0.03 D) and compares very well with the calculated value (mu = 4.14 D). The fact that G:C, I:C, A:T, and DAP:T base pairs are shown to be endowed with distinct van der Waals and electrostatic stacking properties with respect to this heteroaromatic ring system could have important implications for the design of novel DNA mono- and bis-intercalating agents.
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Alcalá de Henares, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Gallego
authors.forename: F J
authors.initials: FJ
authors.lastname: Luque
authors.forename: M
authors.initials: M
authors.lastname: Orozco
authors.forename: C
authors.initials: C
authors.lastname: Burgos
authors.forename: J
authors.initials: J
authors.lastname: Alvarez-Builla
authors.forename: M M
authors.initials: MM
authors.lastname: Rodrigo
authors.forename: F
authors.initials: F
authors.lastname: Gago
mesh_terms: D015075:2-Aminopurine / Q000031:analogs & derivatives; D001482:Base Composition; D001483:Base Sequence; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D003850:Deoxyribonuclease I; D004448:Echinomycin / Q000378:metabolism*; D004563:Electrochemistry; D006860:Hydrogen Bonding; D019271:Hypoxanthine; D007042:Hypoxanthines; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D011810:Quinoxalines / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D007042:Hypoxanthines; D009838:Oligodeoxyribonucleotides; D011810:Quinoxalines; C075619:(N-MeCys(3)-N-MeCys(7))TANDEM; D019271:Hypoxanthine; D015075:2-Aminopurine; C007300:2,6-diaminopurine; D004448:Echinomycin; D004247:DNA; D003850:Deoxyribonuclease I