尿素通过氢键和堆积相互作用保留B-DNA双链体的螺旋完整性，从而模拟了核糖核酸酶。,Biochemistry

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尿素通过氢键和堆积相互作用保留B-DNA双链体的螺旋完整性，从而模拟了核糖核酸酶。
Biochemistry ( IF 2.9 ) Pub Date : 2016-09-29 00:00:00 , DOI: 10.1021/acs.biochem.6b00309
Gorle Suresh ₁ , Siladitya Padhi ₁ , Indrajit Patil ₁ , U. Deva Priyakumar ₁

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由于胸腺嘧啶碱基的自由基损伤，在DNA中形成尿素损害，并且尿素损害在DNA中的存在会阻断DNA聚合酶，从而产生有害后果。最近，已经显示出尿素能够与核碱基形成氢键并堆积相互作用，这是导致RNA在尿素水溶液中展开的原因。碱基配对和堆积是核碱基的固有特性。由于尿素能够同时形成两者，因此本研究试图通过检查引入与四个不同核碱基互补的尿素损伤对B-DNA双链体整体螺旋完整性的影响来研究尿素是否可以在核酸结构的背景下模拟核碱基。使用分子动力学（MD）模拟获得它们的热力学稳定性。MD模拟产生稳定的双链体，而整体B-DNA构象没有明显变化。与实验结果一致，尿素损伤通过与含氮核碱基形成氢键而占据了螺旋内位置。此外，这些尿素损伤与相同和伴侣链的其他核碱基形成氢键键合和堆积相互作用，类似于典型的B-DNA双链体中的核碱基。对于DNA双链体中的脲-嘌呤对，观察到直接氢键相互作用，而对于脲-嘧啶对，观察到两种不同的配对模式，即直接氢键和水介导的氢键。后者解释了解释先前报道的实验核磁共振数据所涉及的复杂性。进一步进行结合自由能计算，以证实结合尿素的DNA双链体相对于纯双链体的热力学稳定性。这项研究表明，尿素通过与所有四个核碱基相对配对来模仿核碱基，并维持B-DNA双链体的整体结构。

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Urea Mimics Nucleobases by Preserving the Helical Integrity of B-DNA Duplexes via Hydrogen Bonding and Stacking Interactions

Urea lesions are formed in DNA because of free radical damage of the thymine base, and their occurrence in DNA blocks DNA polymerases, which has deleterious consequences. Recently, it has been shown that urea is capable of forming hydrogen bonding and stacking interactions with nucleobases, which are responsible for the unfolding of RNA in aqueous urea. Base pairing and stacking are inherent properties of nucleobases; because urea is able to form both, this study attempts to investigate if urea can mimic nucleobases in the context of nucleic acid structures by examining the effect of introducing urea lesions complementary to the four different nucleobases on the overall helical integrity of B-DNA duplexes and their thermodynamic stabilities using molecular dynamics (MD) simulations. The MD simulations resulted in stable duplexes without significant changes in the global B-DNA conformation. The urea lesions occupy intrahelical positions by forming hydrogen bonds with nitrogenous nucleobases, in agreement with experimental results. Furthermore, these urea lesions form hydrogen bonding and stacking interactions with other nucleobases of the same and partner strands, analogous to nucleobases in typical B-DNA duplexes. Direct hydrogen bond interactions are observed for the urea-purine pairs within DNA duplexes, whereas two different modes of pairing, namely, direct hydrogen bonds and water-mediated hydrogen bonds, are observed for the urea-pyrimidine pairs. The latter explains the complexities involved in interpreting the experimental nuclear magnetic resonance data reported previously. Binding free energy calculations were further performed to confirm the thermodynamic stability of the urea-incorporated DNA duplexes with respect to pure duplexes. This study suggests that urea mimics nucleobases by pairing opposite all four nucleobases and maintains the overall structure of the B-DNA duplexes.

更新日期：2016-09-29

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