Unraveling the effects of ubiquitylation on nucleosome assembly and dynamics with coarse-grain simulations.

Abstract

Ubiquitylation of histone proteins remodels and destabilizes the structure, assembly, and dynamics of the nucleosome due to the steric hindrance introduced by the bulky ubiquitin moiety. Histone proteins have multiple ubiquitylation sites, and each appears to have distinct effects on the structure and dynamics of the nucleosome. The spatial dependence of ubiquitin in regulating nucleosome dynamics remains poorly understood due to the non-specific interactions of dyes used in FRET experiments and the poor resolution of ubiquitylated nucleosomes in structural experiments. Using coarse-grain simulations along with Markov State Models, we have studied the reassembly of nucleosome intermediates with canonical and ubiquitylated histones. Results show that the reassembly of hexasomes with ubiquitylated H2A histones at lysine 119 have a destabilized tetramer/dimer interface when compared with the reassembly of hexasomes with canonical histones. Ubiquitin moieties undergo stochastic motions and only form transient interactions with the exit and entry DNA strands. These effects are altered by ubiquitylation at other histone sites, which show distinct effects on nucleosomal structures and dynamics. Together, these results provide a molecular-level understanding of the mechanism by which ubiquitylation location creates distinct effects on the structure and dynamics of the nucleosome and higher-order chromatin structures.