The Free Energy Landscape of Internucleosome Interactions and Its Relation to Chromatin Fiber Structure
The Free Energy Landscape of Internucleosome Interactions and Its Relation to Chromatin Fiber Structure
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DOI：
10.1021/acscentsci.8b00836
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发表时间：
2019-01
影响因子：
18.2
通讯作者：
Joshua Moller;Joshua Lequieu;J. D. de Pablo
中科院分区：
文献类型：
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作者：
Joshua Moller;Joshua Lequieu;J. D. de Pablo
超分子染色质纤维是由分子尺度的能量学和相互作用。这种能量来源于纤维的构建块，核小体核心颗粒（NCP）。近年来，人们通过微扰方法研究了染色质纤维，试图提取纤维中核小体缔合的能量学。这部分工作导致了核小体-核小体能量学实验和模拟的不同结果。在这里，我们扩展了之前的实验，并使用粗粒度模拟来评估核小体在配置和环境空间中的各种参数下固有的能量学。通过这一努力，我们能够揭示对理解30 nm染色质纤维结构至关重要的分子过程。特别是，我们描述的NCP-NCP相互作用依赖于一个各向异性的充满活力的景观，而不是一个单一的势能值。该景观的吸引力主要来自NCP组蛋白N末端结构域（NTD）尾部提供的高度各向异性相互作用。我们的结果被发现是在最近的核小体相互作用实验，建议的最大相互作用能为2.69kBT的良好协议。此外，我们还研究了关键的表观遗传修饰的影响，如H4尾巴的乙酰化，以及它们如何改变潜在的景观。乙酰化NCP相互作用的结果也与实验一致。我们还发现了诱导的手性NCP-NCP相互作用乙酰化后，减少相互作用，这将对应于一个左手的超螺旋染色质纤维。
The supramolecular chromatin fiber is governed by molecular scale energetics and interactions. Such energetics originate from the fiber’s building block, the nucleosome core particle (NCP). In recent years, the chromatin fiber has been examined through perturbative methods in attempts to extract the energetics of nucleosome association in the fiber. This body of work has led to different results from experiments and simulations concerning the nucleosome–nucleosome energetics. Here, we expand on previous experiments and use coarse-grained simulations to evaluate the energetics inherent to nucleosomes across a variety of parameters in configurational and environmental space. Through this effort, we are able to uncover molecular processes that are critical to understanding the 30 nm chromatin fiber structure. In particular, we describe the NCP–NCP interactions by relying on an anisotropic energetic landscape, rather than a single potential energy value. The attractions in that landscape arise predominantly from the highly anisotropic interactions provided by the NCP histone N-terminal domain (NTD) tails. Our results are found to be in good agreement with recent nucleosome interaction experiments that suggest a maximum interaction energy of 2.69kBT. Furthermore, we examine the influence of crucial epigenetic modifications, such as acetylation of the H4 tail, and how they modify the underlying landscape. Our results for acetylated NCP interactions are also in agreement with experiment. We additionally find an induced chirality in NCP–NCP interactions upon acetylation that reduces interactions which would correspond to a left-handed superhelical chromatin fiber.