Determination of a Structural Ensemble Representing the Dynamics of a G-Quadruplex DNA.,Biochemistry

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Determination of a Structural Ensemble Representing the Dynamics of a G-Quadruplex DNA.
Biochemistry ( IF 2.9 ) Pub Date : 2019-12-23 , DOI: 10.1021/acs.biochem.9b00493
Guillem Portella _{1,

2,

3} , Modesto Orozco _{2,

3,

4} , Michele Vendruscolo ₁

Affiliation

It is increasingly recognized that the structures and dynamics of G-quadruplex DNA molecules are dictated by their sequences and greatly affected by environmental factors. The core guanine tetrads (G-tetrads) coordinate cations and display a strong conformational rigidity compared with that of the connecting loops. Although long loops linking the G-tetrads are typically disfavored, when present, they provide a striking illustration of the dynamics of short, single-stranded DNA regions. In addition to their role in determining the stability of the G-quadruplex state, these loops are also interesting as potential drug targets. To characterize accurately the dynamics of this DNA state, we apply here the principles of structural ensemble determination developed in the past two decades for protein molecules to DNA molecules. We thus perform extensive molecular dynamics simulations restrained with nuclear magnetic resonance residual dipolar couplings to determine a structural ensemble of the human CEB25 minisatellite G-quadruplex, which contains a connecting loop of nine nucleotides. This structural ensemble displays a wide set of arrangements for the loop and a compact, well-defined G-quadruplex core. Our results show the importance of stacking interactions in the loop and strengthen the ability of the closing base pairs to confer a large thermodynamic stability to the G-quadruplex structure.

中文翻译：

确定代表G-四链体DNA动力学的结构集合体。

人们日益认识到，G-四链体DNA分子的结构和动力学受其序列支配，并受环境因素的影响很大。与连接环相比，核心鸟嘌呤四联体（G-tetrads）协调阳离子并显示出较强的构象刚度。尽管通常不建议连接G-tetrads的长环，但当存在时，它们为短单链DNA区域的动力学提供了惊人的例证。除了它们在确定G-四链体状态的稳定性中的作用外，这些环作为潜在的药物靶标也很有趣。为了准确地表征这种DNA状态的动力学，我们在这里应用了过去二十年来针对蛋白质分子到DNA分子开发的结构集成测定原理。因此，我们进行了受核磁共振残留偶极耦合约束的广泛分子动力学模拟，以确定人CEB25小卫星G四联体的结构整体，该结构包含9个核苷酸的连接环。这个结构合奏展示了环路的广泛设置和紧凑的，定义明确的G四联体核心。我们的结果表明了在环中堆积相互作用的重要性，并增强了闭合碱基对为G-四链体结构赋予较大的热力学稳定性的能力。这个结构合奏展示了环路的广泛设置和紧凑的，定义明确的G四联体核心。我们的结果表明了在环中堆积相互作用的重要性，并增强了闭合碱基对为G-四链体结构赋予较大的热力学稳定性的能力。这个结构合奏展示了环路的广泛设置和紧凑的，定义明确的G四联体核心。我们的结果表明了在环中堆积相互作用的重要性，并增强了闭合碱基对为G-四链体结构赋予较大的热力学稳定性的能力。

更新日期：2019-12-23

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