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

Sophie E. T. Kendall-Price; Ryan J. O. Nichol; Andrea Taladriz-Sender; Ryan Phelps; Partha Malakar; Gregory M. Greetham; Glenn A. Burley; Neil T. Hunt

doi:10.1021/acs.jpclett.5c01542

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

Sophie E. T. Kendall-Price, Ryan J. O. Nichol, Andrea Taladriz-Sender, Ryan Phelps, Partha Malakar, Gregory M. Greetham, Glenn A. Burley, Neil T. Hunt

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	7875-7882
Number of pages	8
Journal	Journal of Physical Chemistry Letters
Volume	16
Issue number	31
DOIs	https://doi.org/10.1021/acs.jpclett.5c01542
Publication status	Published - 28 Jul 2025

Funding

S.E.T.K-P, R.J.O.N., G.A.B. and N.T.H. gratefully acknowledge funding for this work from the Leverhulme Trust (RPG-2022045). Funding for access to the STFC Central Laser Facility is also acknowledged.

Keywords

genetics
ligands
melting
nucleic acid structure
screening assays

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kendall-price-et-al-2025-long-range-allosteric-modulation-of-dna-duplex-dynamics-induced-by-pyrrole-imidazole-polyamideFinal published version, 5.33 MBLicence: CC BY 4.0

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@article{a209dc5cdb3a4cc2a84c7b7498555ad6,

title = "Long-range allosteric modulation of DNA duplex dynamics induced by pyrrole-imidazole polyamide binding",

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.",

keywords = "genetics, ligands, melting, nucleic acid structure, screening assays",

author = "Kendall-Price, {Sophie E. T.} and Nichol, {Ryan J. O.} and Andrea Taladriz-Sender and Ryan Phelps and Partha Malakar and Greetham, {Gregory M.} and Burley, {Glenn A.} and Hunt, {Neil T.}",

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doi = "10.1021/acs.jpclett.5c01542",

language = "English",

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TY - JOUR

T1 - Long-range allosteric modulation of DNA duplex dynamics induced by pyrrole-imidazole polyamide binding

AU - Kendall-Price, Sophie E. T.

AU - Nichol, Ryan J. O.

AU - Taladriz-Sender, Andrea

AU - Phelps, Ryan

AU - Malakar, Partha

AU - Greetham, Gregory M.

AU - Burley, Glenn A.

AU - Hunt, Neil T.

PY - 2025/7/28

Y1 - 2025/7/28

N2 - 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.

AB - 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.

KW - genetics

KW - ligands

KW - melting

KW - nucleic acid structure

KW - screening assays

U2 - 10.1021/acs.jpclett.5c01542

DO - 10.1021/acs.jpclett.5c01542

M3 - Article

SN - 1948-7185

VL - 16

SP - 7875

EP - 7882

JO - Journal of Physical Chemistry Letters

JF - Journal of Physical Chemistry Letters

IS - 31

ER -

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

Abstract

Funding

Keywords

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