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Hg(II) Binding to Thymine Bases in DNA

Nehzati, Susan LU ; Summers, Anne O. ; Dolgova, Natalia V. ; Zhu, Jianfeng ; Sokaras, Dimosthenis ; Kroll, Thomas ; Pickering, Ingrid J. and George, Graham N. (2021) In Inorganic Chemistry 60(10). p.7442-7452
Abstract

The compounds of mercury can be highly toxic and can interfere with a range of biological processes, although many aspects of the mechanism of toxicity are still obscure or unknown. One especially intriguing property of Hg(II) is its ability to bind DNA directly, making interstrand cross-links between thymine nucleobases in AT-rich sequences. We have used a combination of small molecule X-ray diffraction, X-ray spectroscopies, and computational chemistry to study the interactions of Hg(II) with thymine. We find that the energetically preferred mode of thymine binding in DNA is to the N3 and predict only minor distortions of the DNA structure on binding one Hg(II) to two cross-adjacent thymine nucleotides. The preferred geometry is... (More)

The compounds of mercury can be highly toxic and can interfere with a range of biological processes, although many aspects of the mechanism of toxicity are still obscure or unknown. One especially intriguing property of Hg(II) is its ability to bind DNA directly, making interstrand cross-links between thymine nucleobases in AT-rich sequences. We have used a combination of small molecule X-ray diffraction, X-ray spectroscopies, and computational chemistry to study the interactions of Hg(II) with thymine. We find that the energetically preferred mode of thymine binding in DNA is to the N3 and predict only minor distortions of the DNA structure on binding one Hg(II) to two cross-adjacent thymine nucleotides. The preferred geometry is predicted to be twisted away from coplanar through a torsion angle of between 32 and 43°. Using 1-methylthymine as a model, the bis-thymine coordination of Hg(II) is found to give a highly characteristic X-ray spectroscopic signature that is quite distinct from other previously described biological modes of binding of Hg(II). This work enlarges and deepens our view of significant biological targets of Hg(II) and demonstrates tools that can provide a characteristic signature for the binding of Hg(II) to DNA in more complex matrices including intact cells and tissues, laying the foundation for future studies of mechanisms of mercury toxicity.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
in
Inorganic Chemistry
volume
60
issue
10
pages
11 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85106528246
  • pmid:33938732
ISSN
1520-510X
DOI
10.1021/acs.inorgchem.1c00735
language
English
LU publication?
no
id
1406ed14-04fa-4aa2-a5b0-18b3c5c40556
date added to LUP
2021-05-12 17:19:04
date last changed
2024-06-15 11:10:09
@article{1406ed14-04fa-4aa2-a5b0-18b3c5c40556,
  abstract     = {{<p>The compounds of mercury can be highly toxic and can interfere with a range of biological processes, although many aspects of the mechanism of toxicity are still obscure or unknown. One especially intriguing property of Hg(II) is its ability to bind DNA directly, making interstrand cross-links between thymine nucleobases in AT-rich sequences. We have used a combination of small molecule X-ray diffraction, X-ray spectroscopies, and computational chemistry to study the interactions of Hg(II) with thymine. We find that the energetically preferred mode of thymine binding in DNA is to the N3 and predict only minor distortions of the DNA structure on binding one Hg(II) to two cross-adjacent thymine nucleotides. The preferred geometry is predicted to be twisted away from coplanar through a torsion angle of between 32 and 43°. Using 1-methylthymine as a model, the bis-thymine coordination of Hg(II) is found to give a highly characteristic X-ray spectroscopic signature that is quite distinct from other previously described biological modes of binding of Hg(II). This work enlarges and deepens our view of significant biological targets of Hg(II) and demonstrates tools that can provide a characteristic signature for the binding of Hg(II) to DNA in more complex matrices including intact cells and tissues, laying the foundation for future studies of mechanisms of mercury toxicity.</p>}},
  author       = {{Nehzati, Susan and Summers, Anne O. and Dolgova, Natalia V. and Zhu, Jianfeng and Sokaras, Dimosthenis and Kroll, Thomas and Pickering, Ingrid J. and George, Graham N.}},
  issn         = {{1520-510X}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{7442--7452}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Inorganic Chemistry}},
  title        = {{Hg(II) Binding to Thymine Bases in DNA}},
  url          = {{http://dx.doi.org/10.1021/acs.inorgchem.1c00735}},
  doi          = {{10.1021/acs.inorgchem.1c00735}},
  volume       = {{60}},
  year         = {{2021}},
}