Abstract
Little is known about the roles of histone tails in modulating nucleosomal DNA accessibility and its recognition by other macromolecules. Here we generate extensive atomic level conformational ensembles of histone tails in the context of the full nucleosome, totaling 65 microseconds of molecular dynamics simulations. We observe rapid conformational transitions between tail bound and unbound states, and characterize kinetic and thermodynamic properties of histone tail-DNA interactions. Different histone types exhibit distinct binding modes to specific DNA regions. Using a comprehensive set of experimental nucleosome complexes, we find that the majority of them target mutually exclusive regions with histone tails on nucleosomal/linker DNA around the super-helical locations ± 1, ± 2, and ± 7, and histone tails H3 and H4 contribute most to this process. These findings are explained within competitive binding and tail displacement models. Finally, we demonstrate the crosstalk between different histone tail post-translational modifications and mutations; those which change charge, suppress tail-DNA interactions and enhance histone tail dynamics and DNA accessibility.
Highlights
Little is known about the roles of histone tails in modulating nucleosomal DNA accessibility and its recognition by other macromolecules
Our simulations using the optimal point charge (OPC) water model show many rapid interconversions between tail–DNA bound and unbound states (Fig. 1), pointing to a more dynamic histone tail behavior compared to simulations with the TIP3P water model where histone tails remain in the bound state with DNA most of the time (Supplementary Note 1)[11,18]
Thereafter throughout the paper, we only report the results of simulations with the OPC water model
Summary
Little is known about the roles of histone tails in modulating nucleosomal DNA accessibility and its recognition by other macromolecules. There are very few studies systematically characterizing the histone tail conformational ensemble in the context of the full nucleosome, physicochemical properties of their binding to DNA, and their functional roles in regulatory mechanisms[11,12,21,22]. This is explained by the difficulty in experimentally observing and simulating the intrinsically disordered tails’ conformational space in the context of the full nucleosome. We find that many chromatin factors and histone tails target overlapping and mutually exclusive regions on nucleosomal or linker DNA, pointing to generalized competitive binding or tail displacement mechanisms in nucleosome recognition by binding partners. Our study further demonstrates that posttranslational modifications (PTMs) and mutations in histone tails can alter the tail–DNA binding modes and regulate the binding of partners to the nucleosome
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