4.7 Article

Free Energy Landscape of H2A-H2B Displacement From Nucleosome

期刊

JOURNAL OF MOLECULAR BIOLOGY
卷 434, 期 16, 页码 -

出版社

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2022.167707

关键词

H2A-H2B displacement; Free energy; Nucleosome; Intra-nucleosomal interfaces

资金

  1. Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [hp210177]
  2. Kyoto University [hp210060]
  3. JSPS KAKENHI [JP18K06173, JP18H05534]

向作者/读者索取更多资源

Nucleosome reconstitution is crucial for cellular functions, and the displacement of the H2A-H2B dimer is a key step. In this study, adaptive biased molecular dynamics and umbrella sampling simulations were used to investigate the free energy landscape of the dimer displacement. The docking domain of H2A and the C-terminal of H4 were identified as the main contributors to the free energy. The extent of nucleosomal DNA wrapping determined the different paths for the dimer displacement, suggesting that external factors such as histone chaperones can modulate the displacement path. Additionally, key residues involved in the free energy were found to be related to nucleosome assembly, reassembly, and posttranslational modifications (PTMs) in cancer cells.
Nucleosome reconstitution plays an important role in many cellular functions. As an initial step, H2A-H2B dimer displacement, which is accompanied by disruption of many of the interactions within the nucleosome, should occur. To understand how H2A-H2B dimer displacement occurs, an adaptively biased molecular dynamics (ABMD) simulation was carried out to generate a variety of displacements of the H2A-H2B dimer from the fully wrapped to partially unwrapped nucleosome structures. With regards to these structures, the free energy landscape of the dimer displacement was investigated using umbrella sampling simulations. We found that the main contributors to the free energy were the docking domain of H2A and the C-terminal of H4. There were various paths for the dimer displacement which were dependent on the extent of nucleosomal DNA wrapping, suggesting that modulation of the intra-nucleosomal interaction by external factors such as histone chaperons could control the path for the H2A-H2B dimer displacement. Key residues which contributed to the free energy have also been reported to be involved in the mutations and posttranslational modifications (PTMs) which are important for assembling and/or reassembling the nucleosome at the molecular level and are found in cancer cells at the phenotypic level. Our results give insight into how the H2A-H2B dimer displacement proceeds along various paths according to different interactions within the nucleosome.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据