Coupling between Histone Conformations and DNA Geometry in Nucleosomes on a Microsecond Timescale: Atomistic Insights into Nucleosome Functions

Abstract

An octamer of histone proteins wraps about 200 base pairs of DNA into two super-helical turns to form nucleosomes found in chromatin. Although the static structure of the nucleosomal core particle has been solved, details of the dynamic interactions between histones and DNA remain elusive. We performed extensively long unconstrained, all-atom microsecond molecular dynamics simulations of nucleosomes including linker DNA segments and full-length histones in explicit solvent. For the first time we were able to identify and characterize the rearrangements in nucleosomes on a microsecond timescale including the coupling between the conformation of the histone tails and the DNA geometry. We found that certain histone tail conformations promoted DNA bulging near its entry/exit sites, resulting in the formation of twist-defects within the DNA. This led to a reorganization of histone-DNA interactions, suggestive of the formation of initial nucleosome sliding intermediates. We characterized the dynamics of the histone tails upon their condensation on the core and linker DNA and showed that tails may adopt conformationally constrained positions due to the insertion of “anchoring” lysines and arginines into the DNA minor grooves. Potentially, these phenomena affect the accessibility of post-translationally modified histone residues which serve as important sites for epigenetic marks (e.g. at H3K9, H3K27, H4K16), suggesting that interactions of the histone tails with the core and linker DNA modulate the processes of histone tail modifications and binding of the effector proteins. We discuss the implications of the observed results on the nucleosome function and compare our results to different experimental studies.

Histone H3K4 and H3K36 Methylation Independently Recruit the NuA3 Histone Acetyltransferase in Saccharomyces cerevisiae

“…Instead, these results suggest that there is a level of regulation of histone acetylation that is independent of HAT recruitment. Molecular simulation studies predict histone tails to be tightly intertwined with nucleosomal DNA (Li and Kono 2016;Shaytan et al 2016), and thus disruption of these interactions may be required for acetylation by available HATs. Interestingly, although RNAPII is also found across gene bodies, NET-seq and photoactivatable ribonucleosideenhanced cross-linking and IP experiments show that RNAPII struggles to transcribe through the 59 ends of genes (Churchman and Weissman 2011;Schaughency et al 2014), where the majority of histone acetylation is found.…”

Exploring the Free Energy Landscape of Nucleosomes

“…In fact, atomistic simulations have already provided structural insight into the transient DNA unwrapping near its entry/exit sites, [21][22][23] and revealed the effect of post-translational modifications and different histone variants on nucleosomal dynamics. 22,24 The minimal systems are large in size, and involve a complex ensemble of molecular players having intricate physicochemical interactions.…”

Partially Assembled Nucleosome Structures at Atomic Detail

“…We use, to our knowledge, a novel approach-a combination of modern molecular modeling techniques (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46) and atomic force microscopy (AFM) measurements-to add experimentally consistent models of these three new members to the family of atomistic structures of the nucleosome particles. …”