Department of Molecular and Quantum Biophysics, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
Department of Molecular Biotechnology and Bioinformatics, Institute of High Technologies, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
PLoS One. 2018 Jun 27;13(6):e0199044. doi: 10.1371/journal.pone.0199044. eCollection 2018.
In this paper we have theoretically predicted a novel pathway for the mutagenic tautomerization of the classical A∙T DNA base pairs in the free state, the Watson-Crick A·Т(WC), reverse Watson-Crick A·Т(rWC), Hoogsteen A·Т(H) and reverse Hoogsteen A·Т(rH) pairs, via sequential proton transfer accompanied by a significant change in the mutual orientation of the bases. Quantum-mechanical (QM) calculations were performed at the MP2/aug-cc-pVDZ//B3LYP/6-311++G(d,p) level in vacuum phase, along with Bader's quantum theory of Atoms in Molecules (QTAIM). These processes involve transition states (TSs) with quasi-orthogonal structures (symmetry C1), which are highly polar, tight ion pairs (A-, N6H2-deprotonated)∙(T+, O4/O2-protonated). Gibbs free energies of activation for the A∙T(WC) / A∙T(rWC) ↔ A*∙Т(rwWC) / A*∙Т(wWC) tautomeric transitions (43.5 kcal∙mol-1) are lower than for the A∙T(H) / A∙T(rH) ↔ AN7∙Т(rwH) / AN7∙Т(wH) tautomerisations (53.0 kcal∙mol-1) (rare tautomers are marked by an asterisk; w-wobble configured tautomerisation products). The (T)N3+H⋯N1-(A), (T)O4+H⋯N1-(A) / (T)N3+H⋯N1-(A) and (T)O2+H⋯N1-(A) H-bonds are found in the transition states TSA-·T+A·T(WC)↔A*·T(rwWC) / TSA-·T+A·T(rWC)↔A*·T(wWC). However, in the transition state TSA-·T+A·Т(H)↔AN7·T(rwH) / TSA-·T+A·Т(rH)↔AN7·T(wH), the (T)N3+H⋯N7-(A), (T)O4+H⋯N7-(A) / (T)N3+H⋯N7-(A) and (T)O2+H⋯N7-(A) H-bonds are supplemented by the attractive (T)O4+/O2+⋯N6-(A) van der Waals contacts. It was demonstrated that the products of the tautomerization of the classical A∙T DNA base pairs-A*∙Т(rwWC), AN7∙Т(rwH) and AN7∙Т(wH) (symmetry Cs)-further transform via double proton transfer into the energetically favorable wobble A∙T*(rwWC), A∙T*(rwH) and A∙T*O2(wH) base mispairs (symmetry Cs).
在本文中，我们从理论上预测了经典 A∙T DNA 碱基对在自由状态下的突变互变异构途径，即 Watson-Crick A·Т(WC)、反向 Watson-Crick A·Т(rWC)、Hoogsteen A·Т(H) 和反向 Hoogsteen A·Т(rH) 对，通过连续的质子转移伴随着碱基相互取向的显著变化。在真空相中，使用 MP2/aug-cc-pVDZ//B3LYP/6-311++G(d,p) 水平进行了量子力学(QM)计算，并结合了 Bader 的分子中原子的量子理论(QTAIM)。这些过程涉及具有准正交结构的过渡态(TSs)(对称性 C1)，它们是高度极性的、紧密的离子对(A-，N6H2-去质子化)·(T+，O4/O2-质子化)。A∙T(WC)/A∙T(rWC)↔A*∙Т(rwWC)/A*∙Т(wWC)互变异构跃迁的 Gibbs 自由能活化(43.5 kcal·mol-1)低于 A∙T(H)/A∙T(rH)↔AN7∙Т(rwH)/AN7∙Т(wH)互变异构(53.0 kcal·mol-1)(稀有互变异构体用星号标记；w-摆动配置的互变异构产物)。在过渡态 TSA-·T+A·T(WC)↔A*·T(rwWC)/TSA-·T+A·T(rWC)↔A*·T(wWC)中发现了(T)N3+H⋯N1-(A)、(T)O4+H⋯N1-(A)/ (T)N3+H⋯N1-(A)和(T)O2+H⋯N1-(A)氢键。然而，在过渡态 TSA-·T+A·Т(H)↔AN7·T(rwH)/TSA-·T+A·Т(rH)↔AN7·T(wH)中，(T)N3+H⋯N7-(A)、(T)O4+H⋯N7-(A)/ (T)N3+H⋯N7-(A)和(T)O2+H⋯N7-(A)氢键由吸引力(T)O4+/O2+⋯N6-(A)范德华接触补充。结果表明，经典 A∙T DNA 碱基对互变异构产物-A*∙Т(rwWC)、AN7∙Т(rwH)和 AN7∙Т(wH)(对称性 Cs)-进一步通过两次质子转移转化为能量有利的摆动 A∙T*(rwWC)、A∙T*(rwH)和 A∙T*O2(wH)碱基错配(对称性 Cs)。
