Histone N-terminal tails act as electrostatic clamps to mechanically stabilize nucleosomes

Chromatin accessibility is dynamically regulated by DNA–histone interaction stability. Although histone variants and post-translational modifications are known to modulate nucleosome stability, the direct mechanical contribution of histone N-terminal tails remains poorly understood. Here, we integrate solid-state nanopore-based single-molecule force spectroscopy with coarse-grained molecular dynamics (MD) simulations to elucidate the mechanical role of histone tails in nucleosomal DNA stabilization. Nanopore measurements comparing canonical, H3 tail-less, and all tail-less nucleosomes reveal that tail removal significantly lowers the voltage threshold for complete DNA unwinding, indicating weakened DNA-histone interactions. The overall unwinding pathway remains largely unchanged, suggesting that histone tails primarily modulate the energetic barrier for DNA unwrapping rather than the unwinding mechanism itself. MD simulations map tail-DNA contact frequencies along superhelical locations, showing that the H3 N-terminal tail preferentially stabilizes DNA near SHL ±6/±7 and the dyad, functioning as an electrostatic clamp that suppresses initial DNA unwrapping under low external force. Together, these results establish histone N-terminal tails as intrinsic mechanical stabilizers that regulate chromatin accessibility by tuning the energy landscape of DNA unwinding, providing a quantitative framework for understanding tail-mediated epigenetic regulation.