The Role of Histone Tails in the Nucleosome: A Computational Study
The Role of Histone Tails in the Nucleosome: A Computational Study
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DOI：
10.1016/j.bpj.2014.10.065
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发表时间：
2014-12-16
影响因子：
3.4
通讯作者：
Langowski, Joerg
中科院分区：
文献类型：
--
作者：
Erler, Jochen;Zhang, Ruihan;Langowski, Joerg
组蛋白尾部在基因转录和表达中起着重要作用。我们在这里提出了一个系统的计算研究组蛋白尾部在核小体中的作用，使用带有隐式溶剂模型和不同已建立的力场的复制交换分子动力学模拟。我们对所有四个组蛋白尾部进行了模拟，H4, H3， H2A和H2B，分离并包含核小体。结果证实了先前理论研究对孤立尾的二次结构的预测，但显示出对所使用的力场的强烈依赖。在整个核小体存在的所有力场，组蛋白尾部的二级结构是不稳定的。在带电荷的赖氨酸和精氨酸残基与DNA磷酸基团和其他次要和主要DNA凹槽中的结合位点之间发现了特定的接触。通过聚类分析，我们发现H4和H2A组蛋白尾部与DNA的结合具有单一的优势构型，而H3和H2B组蛋白尾部具有相同概率的多重结合构型。这些结合构型的主要稳定因素是带正电的赖氨酸和精氨酸残基与带负电的磷酸基之间的相互作用，从而产生电荷中和。最后，我们给出了在显式溶剂中的分子动力学模拟结果来证实我们的结论。隐式和显式溶剂模型的结果表明，大部分组蛋白尾部不与DNA结合，支持这些尾部在基因转录和表达中的复杂作用，并使其成为转录因子、酶和其他蛋白质结合位点的可能候选者。
Histone tails play an important role in gene transcription and expression. We present here a systematic computational study of the role of histone tails in the nucleosome, using replica exchange molecular dynamics simulations with an implicit solvent model and different well-established force fields. We performed simulations for all four histone tails, H4, H3, H2A, and H2B, isolated and with inclusion of the nucleosome. The results confirm predictions of previous theoretical studies for the secondary structure of the isolated tails but show a strong dependence on the force field used. In the presence of the entire nucleosome for all force fields, the secondary structure of the histone tails is destabilized. Specific contacts are found between charged lysine and arginine residues and DNA phosphate groups and other binding sites in the minor and major DNA grooves. Using cluster analysis, we found a single dominant configuration of binding to DNA for the H4 and H2A histone tails, whereas H3 and H2B show multiple binding configurations with an equal probability. The leading stabilizing contribution for those binding configurations is the attractive interaction between the positively charged lysine and arginine residues and the negatively charged phosphate groups, and thus the resulting charge neutralization. Finally, we present results of molecular dynamics simulations in explicit solvent to confirm our conclusions. Results from both implicit and explicit solvent models show that large portions of the histone tails are not bound to DNA, supporting the complex role of these tails in gene transcription and expression and making them possible candidates for binding sites of transcription factors, enzymes, and other proteins.