Department of Chemistry & Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta, Canada T1K 3M4.
Phys Chem Chem Phys. 2012 Feb 28;14(8):2743-53. doi: 10.1039/c2cp23600a. Epub 2012 Jan 23.
A computational model composed of six nucleobases was used to investigate why hypoxanthine does not yield duplexes of equal stability when paired opposite each of the natural DNA nucleobases. The magnitudes of all nearest-neighbor interactions in a DNA helix were calculated, including hydrogen-bonding, intra- and interstrand stacking interactions, as well as 1-3 intrastrand stacking interactions. Although the stacking interactions in DNA relevant arrangements are significant and account for at least one third of the total stabilization energy in our nucleobase complexes, the trends in the magnitude of the stacking interactions cannot explain the relative experimental melting temperatures previously reported in the literature. Furthermore, although the total hydrogen-bonding interactions explain why hypoxanthine preferentially pairs with cytosine, the experimental trend for the remaining nucleobases (A, T, G) is not explained. In fact, the calculated pairing preference of hypoxanthine matches that determined experimentally only when the sum of all types of nearest-neighbor interactions is considered. This finding highlights a strong correlation between the relative magnitude of the total nucleobase-nucleobase interactions and measured melting temperatures for DNA strands containing hypoxanthine despite the potential role of other factors (including hydration, temperature, sugar-phosphate backbone). By considering a large range of sequence combinations, we reveal that the binding preference of hypoxanthine is strongly dependent on the nucleobase sequence, which may explain the varied ability of hypoxanthine to universally bind to the natural bases. As a result, we propose that future work should closely examine the interplay between the dominant nucleobase-nucleobase interactions and the overall strand stability to fully understand how sequence context affects the universal binding properties of modified bases and to aid the design of new molecules with ambiguous pairing properties.
使用由六个碱基组成的计算模型研究了为什么次黄嘌呤与天然 DNA 碱基配对时不会产生稳定性相等的双链。计算了 DNA 螺旋中所有最近邻相互作用的大小，包括氢键、碱基对内和碱基对外的堆积相互作用，以及 1-3 个碱基对内的堆积相互作用。尽管在 DNA 相关排列中，堆积相互作用非常重要，并且至少占碱基对复合物总稳定能的三分之一，但堆积相互作用的大小趋势不能解释文献中先前报道的相对实验熔解温度。此外，尽管总氢键相互作用解释了为什么次黄嘌呤优先与胞嘧啶配对，但其余碱基（A、T、G）的实验趋势无法解释。事实上，只有当考虑所有类型的最近邻相互作用的总和时，次黄嘌呤的计算配对偏好才与实验确定的偏好相匹配。这一发现强调了在包含次黄嘌呤的 DNA 链中，碱基对总相互作用的相对大小与测量的熔解温度之间存在很强的相关性，尽管其他因素（包括水合作用、温度、糖-磷酸主链）可能发挥作用。通过考虑大范围的序列组合，我们揭示了次黄嘌呤的结合偏好强烈依赖于碱基序列，这可能解释了次黄嘌呤普遍与天然碱基结合的不同能力。因此，我们建议未来的工作应密切检查主导碱基对相互作用与整体链稳定性之间的相互作用，以充分了解序列上下文如何影响修饰碱基的通用结合特性，并有助于设计具有模糊配对特性的新分子。
