Seeing Supercoiled DNA with Atomistic Simulation: A New Twist on a Familiar Structure
Seeing Supercoiled DNA with Atomistic Simulation: A New Twist on a Familiar Structure
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通过原子模拟观察超螺旋 DNA：熟悉结构的新转折
DOI：
10.1016/j.bpj.2017.11.111
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发表时间：
2018
影响因子：
3.4
通讯作者：
Harris S
中科院分区：
文献类型：
--
作者：
Harris S
双链DNA结构的发现揭示了细胞如何储存遗传信息。然而，我们还远远没有理解更复杂的生物学问题，即细胞如何调节和处理这些信息。当基因转录时，DNA超螺旋产生，并且需要复杂的细胞机制，如拓扑异构酶来调节这种诱导的扭转应力的作用。超螺旋化与原核和真核DNA的包装和3D排列有关，这反过来又对转录调控和基因组稳定性产生根本性影响。尽管超螺旋DNA在细胞中无处不在，但没有实验工具能够捕获原子详细的结构信息。然而，含有100至400个碱基对的小DNA环提供了一个可控的模型系统，用于通过低温电子显微镜、原子力显微镜和计算机建模系统地探索DNA结构对超螺旋的依赖性。我们使用原子分子动力学模拟来探索超螺旋依赖的小DNA环的构象。我们表明，扭结和变性气泡中产生的DNA高扭转应力，DNA的压实是高度依赖于盐，DNA采用扭曲的结构，是高度动态的，并提供额外的机会，DNA/蛋白质在3D空间的相互作用。然后，我们提供了一个原子的解释越来越多的实验数据，显示在基因组中的超螺旋提出的监管作用。
The discovery of the structure of duplex DNA revealed how cells store genetic information. However, we are far from understanding the more complex biological question of how this information is regulated and processed by the cell. DNA supercoiling is generated whenever a gene is transcribed, and complex cellular machinery, such as toposisomerases, are required to modulate the effect of this induced torsional stress. Supercoiling has been implicated in the packaging and 3D arrangement of both prokaryotic and eukaryotic DNA, which in turn has fundamental consequences for transcription regulation and genome stability. In spite of the ubiquity of supercoiled DNA in cells, no experimental tool has been able to capture atomically detailed structural information. Small DNA circles containing between 100 and 400 base pairs, however, offer a controllable model system for the systematic exploration of the dependence of DNA structure on supercoiling through cryo-electron microscopy, atomic force microscopy, and computer modelling. We use atomistic molecular dynamics simulations to explore the supercoiling-dependent conformation of small DNA circles. We show that kinks and denaturation bubbles are generated in the DNA by high torsional stress, that the compaction of the DNA is highly dependent on salt, and that the DNA adopts writhed structures that are highly dynamic and which offer additional opportunities for DNA/protein interactions in 3D space. We then offer an atomistic interpretation for the growing experimental data that shows the regulatory role proposed for supercoiling in the genome.