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Effects of macroH2A and H2A.Z on nucleosome structure and dynamics as elucidated by molecular dynamics simulations

Eukaryotes tune the transcriptional activity of their genome by altering the nucleosome core particle through multiple chemical processes. In particular, replacement of the canonical H2A histone with the variants macroH2A and H2A.Z has been shown to affect DNA accessibility and nucleosome stability; however, the processes by which this occurs remain poorly understood. Here, we elucidate the molecular mechanisms of these variants with an extensive molecular dynamics study of the canonical nucleosome along with three variant-containing structures: H2A.Z, macroH2A, and an H2A mutant with macroH2A-like L1 loops. Simulation results show that variant L1 loops play a pivotal role in stabilizing DNA binding to the octamer through direct interactions, core structural rearrangements, and altered allosteric networks in the nucleosome. All variants influence dynamics; however, macroH2A-like systems have the largest effect on energetics. In addition, we provide a comprehensive analysis of allosteric networks in the nucleosome and demonstrate that variants take advantage of stronger interactions between L1 loops to propagate dynamics throughout the complex. Furthermore, we show that post-translational modifications are enriched at key locations in these networks. Taken together, these results provide new insights into the relationship between the structure, dynamics, and function of the nucleosome core particle and chromatin fibers, and how they are influenced by chromatin remodelling factors.