Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad 500 032, India.
Int J Mol Sci. 2021 May 21;22(11):5411. doi: 10.3390/ijms22115411.
Energetically unfavorable Watson-Crick (WC)-like tautomeric forms of nucleobases are known to introduce spontaneous mutations, and contribute to replication, transcription, and translation errors. Recent NMR relaxation dispersion techniques were able to show that wobble (w) G•U mispair exists in equilibrium with the short-lived, low-population WC-like enolic tautomers. Presently, we have investigated the wG•U → WC-like enolic reaction pathway using various theoretical methods: quantum mechanics (QM), molecular dynamics (MD), and combined quantum mechanics/molecular mechanics (QM/MM). The previous studies on QM gas phase calculations were inconsistent with experimental data. We have also explored the environmental effects on the reaction energies by adding explicit water. While the QM-profile clearly becomes endoergic in the presence of water, the QM/MM-profile remains consistently endoergic in the presence and absence of water. Hence, by including microsolvation and QM/MM calculations, the experimental data can be explained. For the G•Uenol→ Genol•U pathway, the latter appears to be energetically more favorable throughout all computational models. This study can be considered as a benchmark of various computational models of wG•U to WC-like tautomerization pathways with and without the environmental effects, and may contribute on further studies of other mispairs as well.
已知核苷酸碱基的能量不利的沃森-克里克（WC）类似互变异构形式会导致自发突变，并导致复制、转录和翻译错误。最近的 NMR 弛豫分散技术能够表明，摆动（w）G•U 错配与短暂存在的、低种群 WC 类似烯醇互变异构体处于平衡状态。目前，我们使用各种理论方法研究了 wG•U→WC 类似烯醇的反应途径：量子力学（QM）、分子动力学（MD）和组合量子力学/分子力学（QM/MM）。先前关于 QM 气相计算的研究与实验数据不一致。我们还通过添加显式水来探索环境对反应能的影响。虽然 QM 谱在存在水的情况下明显变得内禀，但在存在和不存在水的情况下，QM/MM 谱仍然保持内禀。因此，通过包括微溶剂化和 QM/MM 计算，可以解释实验数据。对于 G•Uenol→ Genol•U 途径，在所有计算模型中，后者似乎在能量上更有利。这项研究可以被认为是各种计算模型对 wG•U 到 WC 类似互变异构途径的基准，包括环境影响和没有环境影响的情况，并且可能对其他错配的进一步研究也有贡献。
