Molecular and Environmental Sciences Group, Department of Geological Sciences, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E2, Canada.
Department of Microbiology, University of Georgia, Athens, Georgia 30602, United States.
Inorg Chem. 2021 May 17;60(10):7442-7452. doi: 10.1021/acs.inorgchem.1c00735. Epub 2021 May 3.
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 -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.
汞的化合物可能具有高度毒性，并能干扰一系列生物过程，尽管其毒性的许多机制仍然模糊不清或未知。Hg(II) 的一个特别有趣的特性是它能够直接与 DNA 结合，从而在富含 AT 的序列中使胸腺嘧啶碱基之间形成链间交联。我们使用小分子 X 射线衍射、X 射线光谱学和计算化学的组合来研究 Hg(II)与胸腺嘧啶的相互作用。我们发现，胸腺嘧啶在 DNA 中结合的最有利的模式是与 N3 结合，并预测在结合一个 Hg(II)到两个交叉相邻的胸腺嘧啶核苷酸上时，DNA 结构只有微小的扭曲。预测优先的几何形状是扭曲离开共面，扭转角在 32 到 43 度之间。使用 1-甲基胸腺嘧啶作为模型，发现 Hg(II)的 - 胸腺嘧啶配位给出了一个非常特征的 X 射线光谱特征，与其他以前描述的 Hg(II)的生物结合模式有很大的不同。这项工作扩大并深化了我们对 Hg(II)的重要生物靶标的认识，并展示了可以为 Hg(II)与包括完整细胞和组织在内的更复杂基质中的 DNA 结合提供特征性特征的工具，为未来研究汞毒性的机制奠定了基础。
