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The fundamental unit of eukaryotic chromatin is the nucleosome core particle, a protein/DNA complex that binds ∼147 base pairs of DNA to a histone octamer. These histones-H3, H4, H2A, H2B-form the nucleosome core through a stacked interaction in which two H2A-H2B dimers flank the (H3-H4) 2 tetramer. In vivo, genetic accessibility can be modulated by the substitution of canonical histones with variant proteins that contain the same structural motif but a different amino acid sequence, such as the transcriptional repression-associated macroH2A variant. Previously, Chakravarthy and Luger published a crystal study that showed that H2A substitution is not necessarily required of both H2A moieties, but that in vitro recombination of nucleosomes in the presence of both macroH2A and H2A histone folds results in a hybrid macroH2A-H2A nucleosome with one dimer of each type. Here, we present molecular dynamics simulations of this hybrid construct and compare the results to our previous study on homogeneous H2A- and macroH2A-containing nucleosomes. We find that the hybrid contains a unique set of dynamics that stabilize the interactions between protein constituents and create an altogether more stable nucleosome, both in terms of protein-DNA and protein-protein binding. While dimer-tetramer interactions are asymmetric, as the difference in moieties would suggest, we observe that it is the canonical dimer that is pulled further into the nucleosome core, resulting in more secure dimer-tetramer bonds and a more stable histone core, and we also find significantly more interaction between the dimer subunits. Together, these models provide evidence for hybrid H2A-macroH2A nucleosome formation being not only possible but actually energetically more favorable than a homogeneous construct, with dynamics that are unique from their homogeneous H2A or macroH2A nucleosome counterparts. These effects of hybrid substitution likely propagate into higher-order chromatin structures to hinder transcriptional activity.

Unique Dynamics in Asymmetric macroH2A–H2A Hybrid Nucleosomes Result in Increased Complex Stability