National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD, USA.
Department of Pathology and Molecular Medicine, School of Medicine, Queen's University, Kingston, ON, Canada.
Nat Commun. 2021 Sep 6;12(1):5280. doi: 10.1038/s41467-021-25568-6.
Little is known about the roles of histone tails in modulating nucleosomal DNA accessibility and its recognition by other macromolecules. Here we generate extensive atomic level conformational ensembles of histone tails in the context of the full nucleosome, totaling 65 microseconds of molecular dynamics simulations. We observe rapid conformational transitions between tail bound and unbound states, and characterize kinetic and thermodynamic properties of histone tail-DNA interactions. Different histone types exhibit distinct binding modes to specific DNA regions. Using a comprehensive set of experimental nucleosome complexes, we find that the majority of them target mutually exclusive regions with histone tails on nucleosomal/linker DNA around the super-helical locations ± 1, ± 2, and ± 7, and histone tails H3 and H4 contribute most to this process. These findings are explained within competitive binding and tail displacement models. Finally, we demonstrate the crosstalk between different histone tail post-translational modifications and mutations; those which change charge, suppress tail-DNA interactions and enhance histone tail dynamics and DNA accessibility.
关于组蛋白尾部在调节核小体 DNA 可及性及其被其他大分子识别中的作用，目前知之甚少。在这里，我们在完整核小体的背景下生成了组蛋白尾部的广泛原子水平构象集合，总计进行了 65 微秒的分子动力学模拟。我们观察到尾部结合和未结合状态之间的快速构象转变，并对组蛋白尾部-DNA 相互作用的动力学和热力学性质进行了表征。不同类型的组蛋白表现出与特定 DNA 区域的不同结合模式。使用一套全面的实验核小体复合物，我们发现它们中的大多数都针对在超螺旋位置±1、±2 和±7 处的核小体/连接 DNA 上的特定 DNA 区域具有独特的结合模式，并且 H3 和 H4 组蛋白尾部对这一过程贡献最大。这些发现可以用竞争结合和尾部置换模型来解释。最后，我们展示了不同组蛋白尾部翻译后修饰和突变之间的串扰；这些修饰和突变会改变电荷，抑制尾部-DNA 相互作用，并增强组蛋白尾部的动力学和 DNA 可及性。
