Molecular Basis for Sequence-Specificity of the Ligands Isohelical to DNA Narrow Groove: Role of Hydrogen Bonding and Structural Complementarity

Abstract

According to the models suggested by us earlier [1, 2] the oligopyrrolcarboxamide backbone of the antibiotics netropsin or distamycin A as well as the oligobenzimidazole backbone of the fluorescent dye Hoechst 33258 form helices isogeometric to the DNA helix and are localized in the DNA narrow groove upon binding. Each bound molecule covers 5 successive DNA base pairs. The binding specificity for AT pairs is a consequence of hydrogen-bond formation between the regularly distributed NH groups of these ligands and facing thymine O₂ oxygens and/or adenine N₃ nitrogens in the narrow groove. This model has been confirmed by the X-ray study done by Dickerson’s group [3] and applied by us in the design and synthesis of bis-netropsins, the ligands consisting of oligophyrrolcarboxamide fragments linked by flexible aliphatic or oligopeptide chains. Structural and energetic parameters characterizing the DNA-binding properties of these compounds will be reported and stereochemical criteria for the design of sequence-specific ligands isohelical to DNA will be discussed.