Histone H4 Tails in Nucleosomes: a Fuzzy Interaction with DNA

• Published in: Angewandte Chemie International Edition 2021-03, Vol.60 (12), p.6480-6487
• Main Authors: Rabdano, Sevastyan O., Shannon, Matthew D., Izmailov, Sergei A., Gonzalez Salguero, Nicole, Zandian, Mohamad, Purusottam, Rudra N., Poirier, Michael G., Skrynnikov, Nikolai R., Jaroniec, Christopher P.
• Format: Article
• Language: English
• Subjects: Bonding strength; Chromatin remodeling; Deoxyribonucleic acid; DNA; DNA - chemistry; fuzzy protein–DNA interactions; Histone H4; histone tails; Histones; Histones - chemistry; Hydrogen bonding; Hydrogen bonds; Ionic strength; molecular dynamics; NMR; NMR spectroscopy; Nuclear magnetic resonance; nucleosome; Nucleosomes; Nucleosomes - chemistry; Protein structure; Sodium chloride
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202012046

The interaction of positively charged N‐terminal histone tails with nucleosomal DNA plays an important role in chromatin assembly and regulation, modulating their susceptibility to post‐translational modifications and recognition by chromatin‐binding proteins. Here, we report residue‐specific 15N NMR relaxation rates for histone H4 tails in reconstituted nucleosomes. These data indicate that H4 tails are strongly dynamically disordered, albeit with reduced conformational flexibility compared to a free peptide with the same sequence. Remarkably, the NMR observables were successfully reproduced in a 2‐μs MD trajectory of the nucleosome. This is an important step toward resolving an apparent inconsistency where prior simulations were generally at odds with experimental evidence on conformational dynamics of histone tails. Our findings indicate that histone H4 tails engage in a fuzzy interaction with nucleosomal DNA, underpinned by a variable pattern of short‐lived salt bridges and hydrogen bonds, which persists at low ionic strength (0–100 mM NaCl). 15N relaxation data suggest that amino‐terminal histone H4 tails in reconstituted nucleosome are flexible. This result is rationalized by suitably designed MD simulations, showing that H4 tails are involved in a fuzzy interaction with nucleosomal DNA while retaining their disordered character.