title: Chromatin Unfolding by Epigenetic Modifications Explained by Dramatic Impairment of Internucleosome Interactions: A Multiscale Computational Study.
abstract: Histone tails and their epigenetic modifications play crucial roles in gene expression regulation by altering the architecture of chromatin. However, the structural mechanisms by which histone tails influence the interconversion between active and inactive chromatin remain unknown. Given the technical challenges in obtaining detailed experimental characterizations of the structure of chromatin, multiscale computations offer a promising alternative to model the effect of histone tails on chromatin folding. Here we combine multimicrosecond atomistic molecular dynamics simulations of dinucleosomes and histone tails in explicit solvent and ions, performed with three different state-of-the-art force fields and validated by experimental NMR measurements, with coarse-grained Monte Carlo simulations of 24-nucleosome arrays to describe the conformational landscape of histone tails, their roles in chromatin compaction, and the impact of lysine acetylation, a widespread epigenetic change, on both. We find that while the wild-type tails are highly flexible and disordered, the dramatic increase of secondary-structure order by lysine acetylation unfolds chromatin by decreasing tail availability for crucial fiber-compacting internucleosome interactions. This molecular level description of the effect of histone tails and their charge modifications on chromatin folding explains the sequence sensitivity and underscores the delicate connection between local and global structural and functional effects. Our approach also opens new avenues for multiscale processes of biomolecular complexes.
authors.affiliation: †Chemistry Department, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW United Kingdom.|‡Joint BSC-CRG-IRB Programme on Computational Biology, Institute for Research in Biomedicine, Baldiri i Reixac 19, 08028, Barcelona, Spain.
authors.forename: Rosana
authors.initials: R
authors.lastname: Collepardo-Guevara
authors.affiliation: †Chemistry Department, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW United Kingdom.|‡Joint BSC-CRG-IRB Programme on Computational Biology, Institute for Research in Biomedicine, Baldiri i Reixac 19, 08028, Barcelona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Portella
authors.affiliation: †Chemistry Department, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: †Chemistry Department, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW United Kingdom.
authors.forename: Daan
authors.initials: D
authors.lastname: Frenkel
authors.affiliation: §Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003, United States.|∥Courant Institute of Mathematical Sciences, New York University, 251 Mercer Street, New York, New York 10012, United States.
authors.forename: Tamar
authors.initials: T
authors.lastname: Schlick
authors.affiliation: ‡Joint BSC-CRG-IRB Programme on Computational Biology, Institute for Research in Biomedicine, Baldiri i Reixac 19, 08028, Barcelona, Spain.|⊥Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Avgda Diagonal 643, 08028, Barcelona, Spain.
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
mesh_terms: D000107:Acetylation; D002843:Chromatin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; D008239:Lysine