Free Energy Landscape of H2A-H2B Displacement From Nucleosome

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 chaperones 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.