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 plant homeodomain (PHD) finger and bromodomain of bromodomain PHD-finger transcription factor (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 engagement inducing compaction of the multidomain structure. PHD-finger binding displaces the H3 tail from DNA, increasing H3 tail flexibility and promoting compensatory binding of the H4 tail to nucleosomal DNA. This redistribution of histone-DNA contacts weakens overall hydrogen bonding with DNA, suggesting localized destabilization of the nucleosome core. Despite electrostatic repulsion limiting direct reader-DNA contacts, strong van der Waals interactions with the H3 tail stabilize binding. Our results provide atomistic insight into how BPTF engagement modulates nucleosome structure and may facilitate chromatin remodeling.