The effect of epigenetic modifications on the secondary structures and possible binding positions of the N-terminal tail of histone H3 in the nucleosome: a computational study

Louis L Du Preez,Hugh-G Patterton

doi:10.1007/s00894-017-3308-x

Louis L Du Preez, Hugh-G Patterton

Open Access

https://doi.org/10.1007/s00894-017-3308-x

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Abstract

The roles of histone tails as substrates for reversible chemical modifications and dynamic cognate surfaces for the binding of regulatory proteins are well established. Despite these crucial roles, experimentally derived knowledge of the structure and possible binding sites of histone tails in chromatin is limited. In this study, we utilized molecular dynamics of isolated histone H3 N-terminal peptides to investigate its structure as a function of post-translational modifications that are known to be associated with defined chromatin states. We observed a structural preference for α-helices in isoforms associated with an inactive chromatin state, while isoforms associated with active chromatin states lacked α-helical content. The physicochemical effect of the post-translational modifications was highlighted by the interaction of arginine side-chains with the phosphorylated serine residues in the inactive isoform. We also showed that the isoforms exhibit different tail lengths, and, using molecular docking of the first 15 N-terminal residues of an H3 isoform, identified potential binding sites between the superhelical gyres on the octamer surface, close to the site of DNA entry/exit in the nucleosome. We discuss the possible functional role of the binding of the H3 tail within the nucleosome on both nucleosome and chromatin structure and stability.

Highlights

The genetic material of eukaryotes is packaged in a repeating oligomeric protein–nucleic acid complex known as chromatin [1]
We investigated whether there was a difference in the structure of the tail between a H3 tail modified with an active post-translational modifications (PTMs) pattern (K4Me3, K9Ac, K14Ac, K36Me3), i.e., a pattern observed in euchromatin [27], versus an inactive PTM pattern (K9Me2, S10Pho, K27Me2, S28Pho), i.e., a pattern observed in heterochromatin [28]
We have used molecular dynamics (MD) with an all-atom structure and an explicit water model in the presence of physiological concentrations of monovalent ions to investigate the impact of epigenetic modifications on the structure of the histone H3 N-terminal tail

Summary

Introduction

The genetic material of eukaryotes is packaged in a repeating oligomeric protein–nucleic acid complex known as chromatin [1]. The fundamental structural unit of chromatin is the nucleosome, which is composed of 168 bp of DNA spooled onto the histone octamer of two copies of each of the core histones H2A, H2B, H3, and H4. A single copy of the linker histone H1 is bound to the outside of the structure, at the point of DNA entry/exit in the nucleosome. The structure of the nucleosome core containing 147 bp of DNA and recombinant histones has been elucidated by X-ray crystallography to a resolution of 1.9 Å [2]. In the absence of observed secondary structures and preferential binding positions, the tails are often described as Bunstructured^ [3]

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