The Opposing Roles of H2A and H2B Ubiquitination on Nucleosome Dynamics Revealed by Molecular Simulations

Nucleosome ubiquitination at lysine 119 of histone H2A (H2AK119Ub) and lysine 120 of histone H2B (H2BK120Ub) are prominent post-translational modifications with opposing roles in chromatin regulation. While H2AK119Ub is associated with transcriptional repression, H2BK120Ub promotes activation, yet the structural mechanisms underlying these effects remain poorly understood due to experimental limitations. To address this, we employed microsecond-scale all-atom molecular dynamics and coarse-grained simulations to investigate the impact of ubiquitination at these sites on nucleosome dynamics. Our results reveal that ubiquitin interacts weakly with DNA in both cases but exhibits higher affinity in H2AK119Ub. Notably, H2AK119Ub stabilizes the nucleosome by strengthening tetramer-dimer and dimer-dimer interactions, particularly at the L1-L1 loop regions, through long-range contacts. In contrast, H2BK120Ub disrupts these interactions, destabilizing the nucleosome and promoting transitions toward hexasomal and tetrasomal states, as observed in coarse-grained nucleosome folding simulations. These findings suggest that ubiquitination directly modulates nucleosome stability and dynamics in a site-dependent manner, providing a mechanistic framework for how chromatin structure is tuned through post-translational modifications.