title: The Acetylation Landscape of the H4 Histone Tail: Disentangling the Interplay between the Specific and Cumulative Effects.
abstract: Histone tails, the intrinsically disordered terminal regions of histone proteins, are key modulators of the structure and dynamics of chromatin and, consequently, are central to many DNA template-directed processes including replication, repair, and transcription. Acetylation of histone tails is a major post-translational modification (PTM) involved in regulating chromatin, yet it remains unclear how acetylation modifies the disordered state of histone tails and affects their function. We investigated the consequences of increasing acetylation on the isolated H4 histone tail by characterizing the conformational ensembles of unacetylated, mono-, di-, tri-, and tetra-acetylated H4 histone tails using Replica Exchange Molecular Dynamics (REMD) simulations. We found that progressive acetylation has a cumulative effect on the H4 tail, decreasing conformational heterogeneity, increasing helical propensity, and increasing hydrogen bond occupancies. The monoacetylation of lysine 16, however, has unique and specific effects: drastically decreasing the conformational heterogeneity of the H4 tail and leading to highly localized helical secondary structure and elongated conformations. We describe how the cumulative effects of acetylation arise from the charge reduction and increased hydrophobicity associated with adding acetyl groups, while the specific effects are a consequence of steric interactions that are sequence specific. Additionally, we found that increasing the level of acetylation results in the formation of spatially clustered lysines that could serve as recognition patches for binding of chromatin regulating proteins. Hence, we explore the mechanisms by which different acetylation patterns may result in specific recognition of the H4 histone tails by protein or DNA binding partners.
authors.affiliation: †Chemical Physics Program and ‡Department of Chemistry and Biochemistry and Institute for Physical Science and Technology, University of Maryland, College Park, Maryland 20742, United States.
authors.forename: David
authors.initials: D
authors.lastname: Winogradoff
authors.affiliation: †Chemical Physics Program and ‡Department of Chemistry and Biochemistry and Institute for Physical Science and Technology, University of Maryland, College Park, Maryland 20742, United States.
authors.forename: Ignacia
authors.initials: I
authors.lastname: Echeverria
authors.affiliation: †Chemical Physics Program and ‡Department of Chemistry and Biochemistry and Institute for Physical Science and Technology, University of Maryland, College Park, Maryland 20742, United States.
authors.forename: Davit A
authors.initials: DA
authors.lastname: Potoyan
authors.affiliation: †Chemical Physics Program and ‡Department of Chemistry and Biochemistry and Institute for Physical Science and Technology, University of Maryland, College Park, Maryland 20742, United States.
authors.forename: Garegin A
authors.initials: GA
authors.lastname: Papoian
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D006657:Histones / Q000737:chemistry*; D008239:Lysine / Q000032:analysis; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011487:Protein Conformation
chemical_list: D006657:Histones; D008239:Lysine