Molecular Modeling and Simulation Group, Department of Quantum Beam Life Science, National Institutes for Quantum and Radiological Science and Technology, Umemidai, Kizugawa, Kyoto, Japan.
Graduate School of Frontier Sciences, The University of Tokyo, Kashiwanoha, Kashiwa, Chiba, Japan.
PLoS Comput Biol. 2018 Mar 5;14(3):e1006024. doi: 10.1371/journal.pcbi.1006024. eCollection 2018 Mar.
The eukaryotic genome is packaged into a nucleus in the form of chromatin. The fundamental structural unit of chromatin is a protein-DNA complex, the nucleosome, where 146 or 147 base pairs of DNA wrap 1.75 times around a histone core. To function in cellular processes, however, nucleosomal DNA must be unwrapped. Although this unwrapping has been experimentally investigated, details of the process at an atomic level are not yet well understood. Here, we used molecular dynamics simulation with an enhanced sampling method to calculate the free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA. A free energy change of about 11.5 kcal/mol for the unwrapping agrees well with values obtained in single molecule experiments. This simulation revealed a variety of conformational states, indicating there are many potential paths to outer superhelicdal turn unwrapping, but the dominant path is likely asymmetric. At one end of the DNA, the first five bps unwrap, after which a second five bps unwrap at the same end with no increase in free energy. The unwrapping then starts at the other end of the DNA, where 10 bps are unwrapped. During further unwrapping of 15 bps, the unwrapping advances at one of the ends, after which the other end of the DNA unwraps to complete the unwrapping of the outer superhelical turn. These results provide insight into the construction, disruption, and repositioning of nucleosomes, which are continuously ongoing during cellular processes.
真核生物的基因组以染色质的形式包装在细胞核内。染色质的基本结构单元是一种蛋白质-DNA 复合物，即核小体，其中 146 或 147 个碱基对的 DNA 缠绕在核心组蛋白周围 1.75 圈。然而，为了在细胞过程中发挥作用，核小体 DNA 必须解旋。尽管已经对这种解旋进行了实验研究，但在原子水平上的过程细节仍未得到很好的理解。在这里，我们使用分子动力学模拟和增强采样方法来计算解开核小体 DNA 外超螺旋的自由能曲线。解开外超螺旋所需的自由能变化约为 11.5 kcal/mol，与单分子实验获得的值非常吻合。该模拟揭示了多种构象状态，表明解开外超螺旋有许多潜在的途径，但主要途径可能是不对称的。在 DNA 的一端，前 5 个碱基对解开，然后在同一端再解开 5 个碱基对，而自由能没有增加。然后，解开过程从 DNA 的另一端开始，其中有 10 个碱基对被解开。在进一步解开 15 个碱基对的过程中，解开过程在 DNA 的一端开始，然后 DNA 的另一端解开，完成外超螺旋的解开。这些结果为核小体的构建、破坏和重新定位提供了深入的了解，这些过程在细胞过程中是持续不断的。
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