BPS2026 – Nucleosome stability is controlled by histone composition and fine-tuned by DNA sequence

Nucleosomes, the building blocks of chromatin, play a central role in controlling DNA accessibility. However, the mechanism by which their chemical composition regulates such regulation is not fully understood. In this study, we apply a near-atomistic coarse-grained model to measure the energetics and uncover the mechanisms of nucleosome unwrapping under applied force across 37 systems, including natural and synthetic DNA sequences, histone variants, and posttranslational modifications such as acetylation. We find that the well-known force barriers associated with the release of the outer and inner DNA turns arise not from simple histone-DNA contact breakage, but from the disruption of partially unwrapped, topologically protected intermediates. In these states, the DNA is misaligned with the pulling force direction, creating temporary resistance until the destabilization that allows contact disruption. The interplay of DNA mechanics, sequence composition, and histone-DNA electrostatics defines these barriers. Remarkably, sequences with high rigidity—although reducing the overall thermodynamic stability of fully wrapped nucleosomes—can enhance mechanical resistance by stabilizing intermediate states. Our analysis also reveals hierarchical histone contributions; arginine-rich residues in the core of H3 and H2A serve as initial anchoring points, while lysine-rich tails, particularly the extended H3 tail, sustain interactions in partially unwrapped configurations and buffer the effects of applied tension. Together, these findings establish a framework that links sequence and histone composition to nucleosome stability, offering new insights into how chromatin encodes both accessibility and mechanical robustness under force.