Brovarets' Ol'ha O, Hovorun Dmytro M
a Department of Molecular and Quantum Biophysics , Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine , 150, Zabolotnoho Str., 03680 , Kyiv , Ukraine .
J Biomol Struct Dyn. 2014;32(9):1474-99. doi: 10.1080/07391102.2013.822829. Epub 2013 Aug 2.
The ground-state tautomerization of the G·C Watson-Crick base pair by the double proton transfer (DPT) was comprehensively studied in vacuo and in the continuum with a low dielectric constant (ϵ = 4), corresponding to a hydrophobic interface of protein-nucleic acid interactions, using DFT and MP2 levels of quantum-mechanical (QM) theory and quantum theory "Atoms in molecules" (QTAIM). Based on the sweeps of the electron-topological, geometric, polar, and energetic parameters, which describe the course of the G·C ↔ G*·C* tautomerization (mutagenic tautomers of the G and C bases are marked with an asterisk) through the DPT along the intrinsic reaction coordinate (IRC), it was proved that it is, strictly speaking, a concerted asynchronous process both at the DFT and MP2 levels of theory, in which protons move with a small time gap in vacuum, while this time delay noticeably increases in the continuum with ϵ = 4. It was demonstrated using the conductor-like polarizable continuum model (CPCM) that the continuum with ϵ = 4 does not qualitatively affect the course of the tautomerization reaction. The DPT in the G·C Watson-Crick base pair occurs without any intermediates both in vacuum and in the continuum with ϵ = 4 at the DFT/MP2 levels of theory. The nine key points along the IRC of the G·C base pair tautomerization, which could be considered as electron-topological "fingerprints" of a concerted asynchronous process of the tautomerization via the DPT, have been identified and fully characterized. These key points have been used to define the reactant, transition state, and product regions of the DPT reaction in the G·C base pair. Analysis of the energetic characteristics of the H-bonds allows us to arrive at a definite conclusion that the middle N1H⋯N3/N3H⋯N1 and the lower N2H⋯O2/N2H⋯O2 parallel H-bonds in the G·C/G*·C* base pairs, respectively, are anticooperative, that is, the strengthening of the middle H-bond is accompanied by the weakening of the lower H-bond. At that point, the upper N4H⋯O6 and O6H⋯N4 H-bonds in the G·C and G*·C* base pairs, respectively, remain constant at the changes of the middle and the lower H-bonds at the beginning and at the ending of the G·C ↔ G*·C* tautomerization. Aiming to answer the question posed in the title of the article, we established that the G*·C* Löwdin's base pair satisfies all the requirements necessary to cause point mutations in DNA except its lifetime, which is much less than the period of time required for the replication machinery to forcibly dissociate a base pair into the monomers (several ns) during DNA replication. So, from the physicochemical point of view, the G*·C* Löwdin's base pair cannot be considered as a source of point mutations arising during DNA replication.
利用密度泛函理论（DFT）和量子力学（QM）理论中的二阶微扰理论（MP2）以及量子理论中的“分子中的原子”（QTAIM），在真空和低介电常数（ϵ = 4）的连续介质中，对G·C沃森 - 克里克碱基对通过双质子转移（DPT）进行的基态互变异构进行了全面研究，该低介电常数对应于蛋白质 - 核酸相互作用的疏水界面。基于电子拓扑、几何、极性和能量参数的扫描，这些参数描述了G·C ↔ G*·C互变异构（G和C碱基的诱变互变异构体用星号标记）通过DPT沿着内禀反应坐标（IRC）的过程，结果证明，严格来说，在DFT和MP2理论水平上，这都是一个协同的异步过程，其中质子在真空中以很小的时间间隔移动，而在ϵ = 4的连续介质中，这个时间延迟会显著增加。使用类导体极化连续介质模型（CPCM）表明，ϵ = 4的连续介质不会定性地影响互变异构反应的过程。在DFT/MP2理论水平上，G·C沃森 - 克里克碱基对中的DPT在真空和ϵ = 4的连续介质中均无任何中间体地发生。已经确定并充分表征了G·C碱基对互变异构IRC上的九个关键点，这些关键点可被视为通过DPT进行互变异构协同异步过程的电子拓扑“指纹”。这些关键点已被用于定义G·C碱基对中DPT反应的反应物、过渡态和产物区域。对氢键能量特征的分析使我们能够得出明确的结论，即G·C/G·C碱基对中中间的N1H⋯N3/N3H⋯N1和较低的N2H⋯O2/N2H⋯O2平行氢键分别是反协同的，也就是说，中间氢键的加强伴随着较低氢键的减弱。此时，在G·C ↔ G·C互变异构开始和结束时，G·C和G·C碱基对中上部的N4H⋯O6和O6H⋯N4氢键在中间和较低氢键变化时保持不变。为了回答文章标题中提出的问题，我们确定G·C洛丁碱基对满足在DNA中引起点突变所需的所有条件，除了其寿命，其寿命远小于DNA复制过程中复制机制将碱基对强行解离成单体所需的时间（几纳秒）。因此，从物理化学角度来看，G·C*洛丁碱基对不能被视为DNA复制过程中产生点突变的来源。
