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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Prototropic tautomerism and basic molecular principles of hypoxanthine mutagenicity: An exhaustive quantum-chemical analysis
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Prototropic tautomerism and basic molecular principles of hypoxanthine mutagenicity: An exhaustive quantum-chemical analysis

机译：质子互变异构和次黄嘌呤致突变性的基本分子原理：详尽的量子化学分析

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The molecular structures, relative stability order, and dipole moments of a complete family of 21 planar hypoxanthine (Hyp) prototropic molecular-zwitterionic tautomers including ylidic forms were computationally investigated at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory in vacuum and in three different surrounding environments: continuum with a low dielectric constant (ε = 4) corresponding to a hydrophobic interface of protein-nucleic acid interactions, dimethylsulfoxide (DMSO), and water. The keto-N1HN7H tautomer was established to be the global minimum in vacuum and in continuum with ε = 4, while Hyp molecule exists as a mixture of the keto-N1HN9H and keto-N1HN7H tautomers in approximately equal amounts in DMSO and in water at T = 298.15 K. We found out that neither intramolecular tautomerization by single proton transfer in the Hyp base, nor intermolecular tautomerization by double proton transfer in the most energetically favorable Hyp·Hyp homodimer (symmetry C2h), stabilized by two equivalent N1H...O6 H-bonds, induces the formation of the enol tautomer (marked with an asterisk) of Hyp with cis-oriented O6H hydroxyl group relative to neighboring N1C6 bond. We first discovered a new scenario of the keto-enol tautomerization of Hyp · Hyp homodimer (C2h) via zwitterionic near-orthogonal transition state (TS), stabilized by N1+H...N1- and O6+H...N 1- H-bonds, to heterodimer Hyp*·Hyp (Cs), stabilized by O6H...O6 and N1H...N1 H-bonds. We first showed that Hyp* · Thy mispair (Cs), stabilized by O6H...O4, N3H...N1, and C2H...O2 H-bonds, mimicking Watson-Crick base pairing, converts to the wobble Hyp* · Thy base pair (Cs), stabilized by N3H...O6 and N1H...O2 H-bonds, via high- and low-energy TSs and intermediate Hyp · Thy*, stabilized by O4H...O6, N1H...N3, and C2H...O2 H-bonds. The most energetically favorable TS is the zwitterionic pair Hyp+ · Thy- (Cs), stabilized by O6+H...O4-, O6+H...N3-, N1+H... N3-, and N1+H...O2- H-bonds. The authors expressed and substantiated the hypothesis, that the keto tautomer of Hyp is a mutagenic compound, while enol tautomer Hyp* does not possess mutagenic properties. The lifetime of the nonmutagenic tautomer Hyp* exceeds by many orders the time needed to complete a round of DNA replication in the cell. For the first time purine-purine planar H-bonded mispairs containing Hyp in the anti-orientation with respect to the sugar moiety - Hyp · Adesyn, Hyp · Gua*syn, and Hyp · Gua*syn, that closely resembles the geometry of the Watson-Crick base pairs, have been suggested as the source of transversions. An influence of the surrounding environment (ε = 4) on the stability of studied complexes and corresponding TSs was estimated by means of the conductor-like polarizable continuum model. Electron-topological, structural, vibrational, and energetic characterictics of all conventional and nonconventional H-bonds in the investigated structures are presented. Presented data are key to understanding elementary molecular mechanisms of mutagenic action of Hyp as a product of the adenine deamination in DNA.
机译：在MP2 / 6-311 ++ G（2df，pd）//上通过计算方法研究了完整的21种平面次黄嘌呤（Hyp）质子性分子-两性离子互变异构体（包括分子型）的分子结构，相对稳定性顺序和偶极矩。 B3LYP / 6-311 ++ G（d，p）在真空中和三种不同周围环境中的理论水平：具有低介电常数（ε= 4）的连续体，对应于蛋白质-核酸相互作用的疏水界面，二甲基亚砜（ DMSO）和水。酮-N1HN7H互变异构体被确定为在真空中且与ε= 4连续时的全局最小值，而Hyp分子以酮-N1HN9H和酮-N1HN7H互变异构体的混合物形式存在，在DMSO和水中的T含量大致相等。 = 298.15K。我们发现，在两个能量相等的N1H ... O6上，无论是在Hyp碱基中通过单质子转移进行的分子内互变异构化，还是在能量上最有利的Hyp·Hyp同型二聚体（对称性C2h）中均未通过双质子转移进行分子间互变异构化。 H键会诱导Hyp的烯醇互变异构体（标有星号）的形成，该Hyp具有相对于相邻N1C6键的顺式O6H羟基。我们首先发现了通过两性离子型近正交过渡态（TS）使Hyp·Hyp同二聚体（C2h）发生酮-烯醇互变异构的新情况，并由N1 + H ... N1-和O6 + H ... N 1稳定-H键，通过O6H ... O6和N1H ... N1 H键稳定到异二聚体Hyp *·Hyp（Cs）。我们首先证明，Hyp *·由O6H ... O4，N3H ... N1和C2H ... O2 H键稳定的Thy不配对（Cs）模仿沃森-克里克碱基配对，转换为摆动Hyp * ·通过高和低能TS和中间Hyp通过N3H ... O6和N1H ... O2 H键稳定的Thy碱基对（Cs），通过O4H ... O6，N1H稳定的Thy *。 ..N3和C2H ... O2 H键。能量最有利的TS是两性离子对Hyp +·Thy-（Cs），由O6 + H ... O4-，O6 + H ... N3-，N1 + H ... N3-和N1 + H稳定... O2- H键作者表达并证实了这一假设，即Hyp的酮互变异构体是一种诱变化合物，而烯醇互变异构体Hyp *不具有诱变特性。非诱变互变异构体Hyp *的寿命超过了在细胞中完成一轮DNA复制所需的时间。首次在相对于糖部分的反方向上含有Hyp的嘌呤-嘌呤平面H键错对-Hyp·Adesyn，Hyp·Gua * syn和Hyp·Gua * syn，与该部分的几何结构极为相似沃森-克里克碱基对被认为是颠换的来源。借助于导体状可极化连续体模型，估计了周围环境（ε= 4）对所研究复合物和相应TSs稳定性的影响。介绍了所研究结构中所有常规和非常规氢键的电子拓扑，结构，振动和能量特征。呈现的数据是理解Hyp诱变作用的基本分子机制的关键，而Hyp是DNA中腺嘌呤脱氨的产物。

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