Histone acetylation is a key regulatory post-translational modification closely associated with gene transcription. In particular, H4K16 acetylation (H4K16ac) is a crucial gene activation marker that induces an open chromatin configuration. While previous studies have explored the effects of H4K16ac on nucleosome interactions, how this local modification affects higher-order chromatin organization remains unclear. To bridge the chemical modifications of these histone tail lysine residues to global chromatin structure, we utilized a residue-resolution coarse-grained chromatin model and enhanced sampling techniques to simulate charge-neutralization effects of histone acetylation on nucleosome stability, internucleosome interactions, and higher-order chromatin structure. Our simulations reveal that H4K16ac stabilizes a single nucleosome due to the reduced entropic contribution of histone tails during DNA unwrapping. In addition, acetylation modestly weakens internucleosome interactions by diminishing contacts between histone tails, DNA, and nucleosome acidic patches. These weakened interactions are amplified when nucleosomes are connected by linker DNA, where increases in linker DNA entry-exit angles lead to significant chromatin destacking and decompaction, exposing nucleosomes to transcriptional activity. Our findings suggest that the geometric constraint imposed by chromatin DNA plays a critical role in driving chromatin structural reorganization upon post-translational modifications.
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