Abstract
Linker histones are epigenetic regulators that bind to nucleosomes and alter chromatin structures and dynamics. Biophysical studies have revealed two binding modes in the linker histone/nucleosome complex, the chromatosome, where the linker histone is either centered on or askew from the dyad axis. Each has been posited to have distinct effects on chromatin, however the molecular and thermodynamic mechanisms that drive them and their dependence on linker histone compositions remain poorly understood. We present molecular dynamics simulations of chromatosomes with the globular domain of two linker histone variants, generic H1 (genGH1) and H1.0 (GH1.0), to determine how their differences influence chromatosome structures, energetics and dynamics. Results show that both unbound linker histones adopt a single compact conformation. Upon binding, DNA flexibility is reduced, resulting in increased chromatosome compaction. While both variants enthalpically favor on-dyad binding, energetic benefits are significantly higher for GH1.0, suggesting that GH1.0 is more capable than genGH1 of overcoming the large entropic reduction required for on-dyad binding which helps rationalize experiments that have consistently demonstrated GH1.0 in on-dyad states but that show genGH1 in both locations. These simulations highlight the thermodynamic basis for different linker histone binding motifs, and details their physical and chemical effects on chromatosomes.
Highlights
In eukaryotes, chromosomes serve as the primary storage medium of genomic information within an organism and consist predominantly of organized, long condensed fibers of DNA and structural proteins [1]
To quantify the dynamics of linker histones in solution, we measured two angles over our unbound genGH1 and GH1.0 simulations, 1 and 2, which were inspired by previous work on GH1.0 by Ozturk et al (Figure 2, left side) [53]
2 angles were more indicative of -loop dynamics with average values of 52.6◦ ± 5.2◦ and 60.2◦ ± 8.9◦ for genGH1 and GH1.0, both of which correspond to closed-states
Summary
Chromosomes serve as the primary storage medium of genomic information within an organism and consist predominantly of organized, long condensed fibers of DNA and structural proteins [1]. The basic building block of chromatin fibers is the nucleosome core particle (NCP) which is comprised of 147 base pairs of DNA wrapped around an octameric core of histone proteins that are built from duplicates of four histones: H2A, H2B, H3 and H4 [1,7,8]. These histones bind to one another to form H2A-H2B and H3-H4 dimers, while the H3H4 dimers associate into a tetramer. This tetramer combines with the H2A-H2B dimers to form the octameric core [9,10]
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