Critical role of histone tail entropy in nucleosome unwinding

Abstract

As the fundamental packaging unit for the genome, the nucleosome is of central importance for many essential biological processes and has been the focus of numerous research efforts. The dynamics of the nucleosome is of particular interest as it must be balanced to maintain long-lasting genome stability while keeping the DNA accessible to protein molecules. Using a transferable protein-DNA model and advanced sampling techniques, we investigated the stability and dynamics of the nucleosome by determining the free energy cost of its DNA unwinding. Simulation results quantitatively reproduce thermodynamic parameters estimated from single-molecule force spectroscopy experiments, and capture the appearance of a large energetic barrier as the system transitions from the outer to the inner layer of DNA unwinding. Analysis of partially unwound nucleosome configurations at atomic resolution revealed that the transition barrier arises from a delayed loss of contacts between histone tails and the DNA. Surprisingly, there is a significant entropic contribution from the same set of disordered tails that largely offset the energetic barrier. Our study greatly improves the current understanding of nucleosome unwinding by providing detailed mechanistic insights into experimental observations.