title: Shearing of the CENP-A dimerization interface mediates plasticity in the octameric centromeric nucleosome.
abstract: The centromeric nucleosome is a key epigenetic determinant of centromere identity and function. Consequently, deciphering how CENP-A containing nucleosomes contribute structurally to centromere function is a fundamental question in chromosome biology. Here, we performed microsecond timescale all-atom molecular dynamics (MD) simulations of CENP-A and H3 nucleosomes, and report that the octameric CENP-A core particles and nucleosomes display different dynamics from their canonical H3-containing counterparts. The most significant motion observed is within key interactions at the heart of the CENP-A octameric core, wherein shearing of contacts within the CENP-A:CENP-A' dimerization interface results in a weaker four helix bundle, and an extrusion of 10-30 bp of DNA near the pseudo-dyad. Coupled to other local and global fluctuations, the CENP-A nucleosome occupies a more rugged free energy landscape than the canonical H3 nucleosome. Taken together, our data suggest that CENP-A encodes enhanced distortability to the octameric nucleosome, which may allow for enhanced flexing of the histone core in vivo.
authors.affiliation: Chemical Physics Program, University of Maryland, College Park, MD 20742, USA.
authors.forename: David
authors.initials: D
authors.lastname: Winogradoff
authors.affiliation: Biophysics Program, University of Maryland, College Park, MD 20742, USA.|Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yamini
authors.initials: Y
authors.lastname: Dalal
authors.affiliation: Chemical Physics Program, University of Maryland, College Park, MD 20742, USA.|Biophysics Program, University of Maryland, College Park, MD 20742, USA.|Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
authors.forename: Garegin A
authors.initials: GA
authors.lastname: Papoian
mesh_terms: D001324:Autoantigens / Q000737:chemistry / Q000378:metabolism*; D002503:Centromere / Q000378:metabolism; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D006657:Histones / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D055672:Static Electricity
chemical_list: D001324:Autoantigens; C000619700:CENPA protein, human; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D009707:Nucleosomes; D004247:DNA