A sequence-specific threading tetra-intercalator with an extremely slow dissociation rate constant
Author: ["Garen G. Holman","Maha Zewail-Foote","Amy Rhoden Smith","Kenneth A. Johnson","Brent L. Iverson"]
Publication: Nature Chemistry
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Abstract
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. Molecules that bind to DNA for extended periods can modulate its transcription or other biological processes. Kinetic studies on the non-covalent complex formed by a threading tetra-intercalator and a DNA double-helix have now revealed a multi-step association, and a particularly slow dissociation leading to sequence specificity and a 16-day half-life.
Cite this article
Holman, G., Zewail-Foote, M., Smith, A. et al. A sequence-specific threading tetra-intercalator with an extremely slow dissociation rate constant. Nature Chem 3, 875–881 (2011). https://doi.org/10.1038/nchem.1151
