Sun Tiedong, Korolev Nikolay, Lyubartsev Alexander P, Nordenskiöld Lars
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Department of Materials and Environmental Chemistry, Stockholm University, Svante Arrhenius väg 16C, Stockholm SE-106 91, Sweden.
J Chem Phys. 2025 Jan 14;162(2). doi: 10.1063/5.0242509.
Eukaryotic DNA is packaged in the cell nucleus into chromatin, composed of arrays of DNA-histone protein octamer complexes, the nucleosomes. Over the past decade, it has become clear that chromatin structure in vivo is not a hierarchy of well-organized folded nucleosome fibers but displays considerable conformational variability and heterogeneity. In vitro and in vivo studies, as well as computational modeling, have revealed that attractive nucleosome-nucleosome interaction with an essential role of nucleosome stacking defines chromatin compaction. The internal structure of compacted nucleosome arrays is regulated by the flexible and dynamic histone N-terminal tails. Since DNA is a highly negatively charged polyelectrolyte, electrostatic forces make a decisive contribution to chromatin formation and require the histones, particularly histone tails, to carry a significant positive charge. This also results in an essential role of mobile cations of the cytoplasm (K+, Na+, Mg2+) in regulating electrostatic interactions. Building on a previously successfully established bottom-up coarse-grained (CG) nucleosome model, we have developed a CG nucleosome array (chromatin fiber) model with the explicit presence of mobile ions and studied its conformational variability as a function of Na+ and Mg2+ ion concentration. With progressively elevated ion concentrations, we identified four main conformational states of nucleosome arrays characterized as extended, flexible, nucleosome-clutched, and globular fibers.
真核生物的DNA在细胞核中被包装成染色质，染色质由DNA-组蛋白八聚体复合物（核小体）阵列组成。在过去十年中，很明显体内染色质结构并非是由组织良好的折叠核小体纤维构成的层级结构，而是表现出相当大的构象变异性和异质性。体外和体内研究以及计算模型表明，具有核小体堆积关键作用的核小体-核小体间吸引力决定了染色质的压缩。压缩核小体阵列的内部结构受灵活且动态的组蛋白N端尾巴调控。由于DNA是高度带负电荷的聚电解质，静电力对染色质形成起决定性作用，这就要求组蛋白，尤其是组蛋白尾巴，携带大量正电荷。这也导致细胞质中的移动阳离子（K⁺、Na⁺、Mg²⁺）在调节静电相互作用中起关键作用。基于之前成功建立的自下而上的粗粒度（CG）核小体模型，我们开发了一种明确包含移动离子的CG核小体阵列（染色质纤维）模型，并研究了其构象变异性与Na⁺和Mg²⁺离子浓度的关系。随着离子浓度逐渐升高，我们确定了核小体阵列的四种主要构象状态，分别为伸展纤维、柔性纤维、核小体簇集纤维和球状纤维。
