Deciphering the Molecular Mechanisms of BPTF Interactions with Nucleosomes via Molecular Simulations

Many transcription factors regulate DNA accessibility and gene expression by recognizing post-translational modifications on histone tails within nucleosomes. These interactions are often studied in vitro using short peptide mimics of histone tails, which may overlook conformational changes that occur in the full nucleosomal context. Here, we employ molecular dynamics simulations to investigate the binding dynamics of the PHD finger and bromodomain of BPTF, both in solution and bound to either a histone H3 peptide or a full nucleosome. Our results show that BPTF adopts distinct conformational states depending on its binding context, with nucleosome-bound BPTF exhibiting altered histone core interactions. Electrostatic repulsion limits direct reader-DNA contacts, while histone-DNA hydrogen bonding decreases, suggesting a shift in nucleosome stability. Our findings indicate that BPTF binding to nucleosomes alters local chromatin architecture, potentially contributing to nucleosome remodeling and gene regulation.