H3 Histone Tail Conformation within the Nucleosome and the Impact of K14 Acetylation Studied Using Enhanced Sampling Simulation

Acetylation of lysine residues in histone tails is associated with gene transcription. Because histone tails are structurally flexible and intrinsically disordered, it is difficult to experimentally determine the tail conformations and the impact of acetylation. In this work, we performed simulations to sample H3 tail conformations with and without acetylation. The results show that irrespective of the presence or absence of the acetylation, the H3 tail remains in contact with the DNA and assumes an α-helix structure in some regions. Acetylation slightly weakened the interaction between the tail and DNA and enhanced α-helix formation, resulting in a more compact tail conformation. We inferred that this compaction induces unwrapping and exposure of the linker DNA, enabling DNA-binding proteins (e.g., transcription factors) to bind to their target sequences. In addition, our simulation also showed that acetylated lysine was more often exposed to the solvent, which is consistent with the fact that acetylation functions as a post-translational modification recognition site marker.Author Summary: Post-translational modification (PTM) of histone tails is an important component of epigenetics. Acetylation of histone tails generally functions to activate gene expression, though the molecular mechanism is not well understood. We used enhanced sampling simulation to examine the impact of acetylation on the structure of the histone H3 tail within the nucleosome. The results suggest acetylation makes the H3 tail conformation more compact and enhances dissociation of nucleosomal DNA from the histone core. Further, the acetylated lysine was more exposed to the solvent, which is consistent with its role as a PTM recognition site marker. These findings increase our understanding of the impact of PTM on nucleosome stability and dynamics and on the higher order structure of chromatin.