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Download fileHg(II) Binding to Thymine Bases in DNA
journal contribution
posted on 03.05.2021, 14:35 authored by Susan Nehzati, Anne O. Summers, Natalia V. Dolgova, Jianfeng Zhu, Dimosthenis Sokaras, Thomas Kroll, Ingrid J. Pickering, Graham N. GeorgeThe
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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Keywords
thymine coordinationmercury toxicitythymine nucleobasesX-ray spectroscopiesbind DNAX-ray spectroscopic signaturemolecule X-ray diffractionAT-rich sequences1- methylthymineHgDNA structureinterstrand cross-linkscross-adjacent thymine nucleotidesfuture studiesThymine Basesthymine bindingN 3torsion angle