Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides

Alice L. B. Pyne (), Agnes Noy (), Kavit H. S. Main, Victor Velasco-Berrelleza, Michael M. Piperakis, Lesley A. Mitchenall, Fiorella M. Cugliandolo, Joseph G. Beton, Clare E. M. Stevenson, Bart W. Hoogenboom, Andrew D. Bates, Anthony Maxwell and Sarah A. Harris ()
Additional contact information
Alice L. B. Pyne: University of Sheffield
Agnes Noy: University of York
Kavit H. S. Main: University College London
Victor Velasco-Berrelleza: University of York
Michael M. Piperakis: John Innes Centre
Lesley A. Mitchenall: John Innes Centre
Fiorella M. Cugliandolo: John Innes Centre
Joseph G. Beton: University College London
Clare E. M. Stevenson: John Innes Centre
Bart W. Hoogenboom: University College London
Andrew D. Bates: University of Liverpool
Anthony Maxwell: John Innes Centre
Sarah A. Harris: University of Leeds

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract In the cell, DNA is arranged into highly-organised and topologically-constrained (supercoiled) structures. It remains unclear how this supercoiling affects the detailed double-helical structure of DNA, largely because of limitations in spatial resolution of the available biophysical tools. Here, we overcome these limitations, by a combination of atomic force microscopy (AFM) and atomistic molecular dynamics (MD) simulations, to resolve structures of negatively-supercoiled DNA minicircles at base-pair resolution. We observe that negative superhelical stress induces local variation in the canonical B-form DNA structure by introducing kinks and defects that affect global minicircle structure and flexibility. We probe how these local and global conformational changes affect DNA interactions through the binding of triplex-forming oligonucleotides to DNA minicircles. We show that the energetics of triplex formation is governed by a delicate balance between electrostatics and bonding interactions. Our results provide mechanistic insight into how DNA supercoiling can affect molecular recognition, that may have broader implications for DNA interactions with other molecular species.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21243-y

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DOI: 10.1038/s41467-021-21243-y

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