Critical role of histone tail entropy in nucleosome unwinding.

The nucleosome is the fundamental packaging unit for the genome. It must remain tightly wound to ensure genome stability while simultaneously being flexible enough to keep the DNA molecule accessible for genome function. The set of physicochemical interactions responsible for the delicate balance between these naturally opposed processes have not been determined due to challenges in resolving partially unwound nucleosome configurations at atomic resolution. Using a near atomistic protein-DNA model and advanced sampling techniques, we calculate the free energy cost of nucleosome DNA unwinding. Our simulations identify a large energetic barrier that decouples the outer and the inner DNA unwinding into two separate processes, occurring on different time scales. This dynamical decoupling allows the exposure of outer DNA at a modest cost to ensure accessibility while keeping the inner DNA and the histone core intact to maintain stability. We also reveal that this energetic barrier arises from a delayed loss of contacts between disordered histone tails and the DNA and is, surprisingly, largely offset by an entropic contribution from these tails. Implications of this enthalpy entropy compensation for the regulation of nucleosome stability and genome function are discussed.