A sequence-specific threading tetra-intercalator with an extremely slow dissociation rate constant.
A long-lived and sequence-specific ligand-DNA complex would make possible the modulation of biological processes for extended periods. For this purpose, we are investigating a polyintercalation approach to DNA recognition in which flexible chains of aromatic units thread back and forth repeatedly through the double helix. Here we describe the DNA-binding behaviour of a threading tetra-intercalator. Specific binding was observed on a relatively long DNA strand that strongly favoured a predicted 14 base-pair sequence. Kinetic studies revealed a multistep association process, with sequence specificity that primarily derives from large differences in dissociation rates. The rate-limiting dissociation rate constant of the tetra-intercalator complex dissociating from its preferred binding site was extremely slow, corresponding to a half-life of 16 days. This is one of the longest non-covalent complex half-lives yet reported and, to the best of our knowledge, the longest for a DNA-binding molecule.
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, USA.
Garen G
GG
Holman
Maha
M
Zewail-Foote
Amy Rhoden
AR
Smith
Kenneth A
KA
Johnson
Brent L
BL
Iverson
D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D007364:Intercalating Agents / Q000737:chemistry*; D007700:Kinetics; D053644:Naphthalimides / Q000138:chemical synthesis / Q000737:chemistry*; D009690:Nucleic Acid Conformation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*
D007364:Intercalating Agents; D053644:Naphthalimides; D010455:Peptides; C568653:amino acetamide-NDI-lysyl-beta-alanyl-beta-alanyl-beta-alanyl-NDI-lysyl-adipamide-lysyl-NDI-beta-alanyl-beta-alanyl-beta-alanyl-lysyl-NDI-amino acetamide; D004247:DNA