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首页> 外文期刊>Journal of Molecular Biology >Coupling between Histone Conformations and DNA Geometry in Nucleosomes on a Microsecond Timescale: Atomistic Insights into Nucleosome Functions
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Coupling between Histone Conformations and DNA Geometry in Nucleosomes on a Microsecond Timescale: Atomistic Insights into Nucleosome Functions

机译：微秒级尺度上的核小体中组蛋白构型与DNA几何之间的耦合：核小体功能的原子学见解。

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An octamer of histone proteins wraps about 200 bp of DNA into two superhelical turns to form nucleosomes found in chromatin. Although the static structure of the nucleosomal core particle has been solved, details of the dynamic interactions between histones and DNA remain elusive. We performed extensively long unconstrained, all-atom microsecond molecular dynamics simulations of nucleosomes including linker DNA segments and full-length histones in explicit solvent. For the first time, we were able to identify and characterize the rearrangements in nucleosomes on a microsecond timescale including the coupling between the conformation of the histone tails and the DNA geometry. We found that certain histone tail conformations promoted DNA bulging near its entry/exit sites, resulting in the formation of twist defects within the DNA. This led to a reorganization of histone-DNA interactions, suggestive of the formation of initial nucleosome sliding intermediates. We characterized the dynamics of the histone tails upon their condensation on the core and linker DNA and showed that tails may adopt conformationally constrained positions due to the insertion of "anchoring" lysines and arginines into the DNA minor grooves. Potentially, these phenomena affect the accessibility of post-translationally modified histone residues that serve as important sites for epigenetic marks (e.g., at H3K9, H3K27, H4K16), suggesting that interactions of the histone tails with the core and linker DNA modulate the processes of histone tail modifications and binding of the effector proteins. We discuss the implications of the observed results on the nucleosome function and compare our results to different experimental studies. Published by Elsevier Ltd.
机译：组蛋白的八聚体将约200 bp的DNA包裹成两个超螺旋匝，形成染色质中的核小体。尽管核小体核心颗粒的静态结构已得到解决，但组蛋白与DNA之间动态相互作用的细节仍然难以捉摸。我们在明确的溶剂中对核小体进行了长时间的，不受约束的全原子微秒分子动力学模拟，包括接头DNA片段和全长组蛋白。我们首次能够在微秒级的时间尺度上鉴定并表征核小体中的重排，包括组蛋白尾部构象与DNA几何结构之间的偶联。我们发现某些组蛋白尾部构象促进了其进入/退出位点附近的DNA凸起，导致DNA内扭曲缺陷的形成。这导致组蛋白-DNA相互作用的重组，暗示了初始核小体滑动中间体的形成。我们表征了组蛋白尾巴在核心和接头DNA上的缩合后的动力学，并显示出由于“锚定”赖氨酸和精氨酸插入DNA小沟而导致尾巴可能采取构象受限的位置。这些现象可能会影响翻译后修饰的组蛋白残基的可及性，后者是表观遗传标记的重要位点（例如，在H3K9，H3K27，H4K16处），表明组蛋白尾巴与核心和接头DNA的相互作用调节了组蛋白尾部修饰和效应蛋白的结合。我们讨论了观察到的结果对核小体功能的影响，并将我们的结果与不同的实验研究进行了比较。由Elsevier Ltd.发布

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