Long-range allosteric modulation of DNA duplex dynamics induced by pyrrole-imidazole polyamide binding

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Kendall-Price, Sophie E. T. and Nichol, Ryan J. O. and Taladriz-Sender, Andrea and Phelps, Ryan and Malakar, Partha and Greetham, Gregory M. and Burley, Glenn A. and Hunt, Neil T. (2025) Long-range allosteric modulation of DNA duplex dynamics induced by pyrrole-imidazole polyamide binding. Journal of Physical Chemistry Letters, 16 (31). pp. 7875-7882. ISSN 1948-7185 (https://doi.org/10.1021/acs.jpclett.5c01542)

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Abstract

The allosteric modulation of the structural dynamics of double-stranded DNA (dsDNA) duplexes as a function of distance from the site of a minor groove binding ligand is reported. Time-resolved temperature-jump infrared spectroscopy is used to interrogate the impact of binding a pyrrole-imidazole polyamide to dsDNA sequences 8–14 base-pairs in length. Our results demonstrate that the binding of the hairpin polyamide to its target site (5′-WWGTACW-3′; W = A/T) causes a marked suppression of structural dynamics, such as end fraying, with suppression observed in both the 3′ and 5′ directions. Quantitative analysis of end fraying suppression reveals a propagation length for dynamic modulation of 30 base-pairs. Identifying the structural impact of minor groove binding to dsDNA sequences furthers our understanding of the influence of dsDNA recognition and informs the design of next-generation synthetic transcription factors.

ORCID iDs

Kendall-Price, Sophie E. T., Nichol, Ryan J. O., Taladriz-Sender, Andrea ORCID logoORCID: https://orcid.org/0000-0002-8274-4761, Phelps, Ryan, Malakar, Partha, Greetham, Gregory M., Burley, Glenn A. ORCID logoORCID: https://orcid.org/0000-0002-4896-113X and Hunt, Neil T. ORCID logoORCID: https://orcid.org/0000-0001-7400-5152;
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