Computer Modeling Reveals that Modifications of the Histone Tail Charges Define Salt-Dependent Interaction of the Nucleosome Core Particles (original) (raw)
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The Influence of Ionic Environment and Histone Tails on Columnar Order of Nucleosome Core Particles
Biophysical journal, 2016
The nucleosome core particle (NCP) is the basic building block of chromatin. Nucleosome-nucleosome interactions are instrumental in chromatin compaction, and understanding NCP self-assembly is important for understanding chromatin structure and dynamics. Recombinant NCPs aggregated by multivalent cations form various ordered phases that can be studied by x-ray diffraction (small-angle x-ray scattering). In this work, the effects on the supramolecular structure of aggregated NCPs due to lysine histone H4 tail acetylations, histone H2A mutations (neutralizing the acidic patch of the histone octamer), and the removal of histone tails were investigated. The formation of ordered mainly hexagonal columnar NCP phases is in agreement with earlier studies; however, the highly homogeneous recombinant NCP systems used in this work display a more compact packing. The long-range order of the NCP columnar phase was found to be abolished or reduced by acetylation of the H4 tails, acidic patch neut...
Structure and Phase Diagram of Nucleosome Core Particles Aggregated by Multivalent Cations
Biophysical Journal, 2007
The degree of compaction of the eukaryotic chromatin in vivo and in vitro is highly sensitive to the ionic environment. We address the question of the effect of multivalent ions on the interactions and mutual organization of the chromatin structural units, the nucleosome core particles (NCPs). Conditions of precipitation of NCPs in the presence of 10 mM Tris buffer and various amounts of either magnesium (Mg 21 ) or spermidine (Spd 31 ) are explored, compared, and discussed in relation to theoretical models. In addition, the structure of the aggregates is analyzed by complementary techniques: freeze-fracture electron microscopy, cryoelectron microscopy, and x-ray diffraction. In Mg 21 -NCP aggregates, NCPs tend to stack on top of one another to form columns that are not long-range organized. In the presence of Spd 31 , NCPs precipitate to form a dense isotropic phase, a disordered phase of columns, a two-dimensional columnar hexagonal phase, or a three-dimensional crystal. The more ordered phases (two-dimensional or three-dimensional hexagonal) are found close to the precipitation line, where the number of positive charges carried by cations is slightly larger than the number of available negative charges of the NCPs. All ordered phases coexist with the dense isotropic phases. Formation of hexagonal and columnar phases is prevented by an excess of polycations.
Electrostatic Origin of Salt-Induced Nucleosome Array Compaction
Biophysical Journal, 2010
The physical mechanism of the folding and unfolding of chromatin is fundamentally related to transcription but is incompletely characterized and not fully understood. We experimentally and theoretically studied chromatin compaction by investigating the salt-mediated folding of an array made of 12 positioning nucleosomes with 177 bp repeat length. Sedimentation velocity measurements were performed to monitor the folding provoked by addition of cations Na þ , K þ , Mg 2þ , Ca 2þ , spermidine 3þ , Co(NH 3) 6 3þ , and spermine 4þ. We found typical polyelectrolyte behavior, with the critical concentration of cation needed to bring about maximal folding covering a range of almost five orders of magnitude (from 2 mM for spermine 4þ to 100 mM for Na þ). A coarse-grained model of the nucleosome array based on a continuum dielectric description and including the explicit presence of mobile ions and charged flexible histone tails was used in computer simulations to investigate the cation-mediated compaction. The results of the simulations with explicit ions are in general agreement with the experimental data, whereas simple Debye-Hü ckel models are intrinsically incapable of describing chromatin array folding by multivalent cations. We conclude that the theoretical description of the salt-induced chromatin folding must incorporate explicit mobile ions that include ion correlation and ion competition effects.
The Journal of Physical Chemistry A, 2009
To elucidate the role of the histone tails in chromatin compaction and in higher-order folding of chromatin under physiological conditions, we extend a mesoscale model of chromatin [Arya, Zhang, and Schlick, Biophys. J. 91, 133 (2006); Arya and Schlick, Proc. Natl. Acad. Sci. USA 103, 16236 (2006)] to account for divalent cations (Mg 2+ ) and linker histones. Configurations of 24-nucleosome oligonucleosomes in different salt environments and in the presence and absence of linker histones are sampled by a mixture of local and global Monte Carlo methods. Analyses of the resulting ensembles reveals a dynamic synergism between the histone tails, linker histones, and physiological ions in forming compact higher-order structures of chromatin. In the presence of monovalent salt alone, oligonucleosomes remain relatively unfolded and the histone tails do not mediate many internucleosomal interactions. Upon the addition of linker histones and divalent cations, the oligonucleosomes undergo a significant compaction triggered by: a dramatic increase in the internucleosomal interactions mediated by the histone tails; formation of a rigid linker DNA "stem" around the linker histones' C-terminal domains; and reducion in the electrostatic repulsion between linker DNAs via sharp bending in some linker DNAs caused by the divalent cations. Among all histone tails, the H4 tails mediate the most internucleosomal interactions, consistent with experimental observations, followed by the H3, H2A, and H2B tails in decreasing order. Apart from mediating internucleosomal interactions, the H3 tails also contribute to chromatin compaction by attaching to the entering and exiting linker DNA to screen electrotatic repulsion among the linker DNAs. This tendency of the H3 tails to attach to linker DNA, however, decreases significantly upon the addition of linker histones due to competition effects. The H2A and H2B tails do not mediate significant internucleosomal interactions but are important for mediating fiber/fiber intractions, especially in relatively unfolded chromatin in monovalent salt environments.
Holding the nucleosome together: A quantitative description of the DNA-histone interface in solution
Journal of chemical theory and computation, 2017
The nucleosome is the fundamental unit of eukaryotic genome packaging in the chromatin. In this complex, the DNA wraps around eight histone proteins to form a super-helical double helix. The resulting bending, stronger than anything observed in free DNA, raises the question to how such a distortion is stabilized by the proteic and solvent environments. In this work, the DNA-histone interface in solution was exhaustively analyzed from nucleosome structures generated by molecular dynamics. An original Voronoi tessellation technique, measuring the topology of interacting elements without any empirical or subjective adjustment, was used to characterize the interface in terms of contact area and occurrence. Our results revealed an interface more robust than previously known, combining extensive, long-lived non-electrostatic and electrostatic interactions between DNA and both structured and unstructured histone regions. Cation accumulation makes the proximity of juxtaposed DNA gyres in th...
H3 and H4 Histone Tails Play a Central Role in the Interactions of Recombinant NCPs
Biophysical Journal, 2007
Using small-angle x-ray scattering, we probe the effect of histone tails on both internucleosomal interactions and nucleosome conformation. To get insight into the specific role of H3 and H4 histone tails, perfectly monodisperse recombinant nucleosome core particles were reconstituted, either intact or deprived of both H3 and H4 histone tails (gH3gH4). The main result is that H3 and H4 histone tails are necessary to induce attractive interactions between NCPs. A pair potential model was used to describe interactions between NCPs. At all salt concentrations, interactions between gH3gH4 NCPs are best described by repulsive interactions exclusively. For intact NCPs, an additional attractive term, with a 5-10 kT magnitude and 20 Å range, is required to account for interparticle interactions above 50 mM monovalent salt. Regarding conformation, intact NCPs in solution are similar to NCPs in 3D crystals. gH3gH4 NCPs instead give rise to slightly different small-angle x-ray scattering curves that can be understood as a more opened conformation of the particle, where DNA ends are slightly detached from the core.
Structural and kinetic study of the self-assembly of nucleosome core particles
Journal of Molecular Biology, 1982
When isolated chicken erythrocyte core histones (or core particles dissociated in 2-O M-N&I) are labeled with the fluorescent reagent N-( I-pyrene)maleimide at pH 7.0, only histone H3 reacts, presumably at cysteine 110. Pyrene-labeled core particles were salt-jumped from 2.0&i-NaCl to lower concentrations.
The role of histone tails in nucleosome stability: An electrostatic perspective
Computational and Structural Biotechnology Journal, 2020
We propose a methodology for the study of protein-DNA electrostatic interactions and apply it to clarify the effect of histone tails in nucleosomes. This method can be used to correlate electrostatic interactions to structural and functional features of protein-DNA systems, and can be combined with coarse-grained representations. In particular, we focus on the electrostatic field and resulting forces acting on the DNA. We investigate the electrostatic origins of effects such as different stages in DNA unwrapping, nucleosome destabilization upon histone tail truncation, and the role of specific arginines and lysines undergoing Post-Translational Modifications. We find that the positioning of the histone tails can oppose the attractive pull of the histone core, locally deform the DNA, and tune DNA unwrapping. Small conformational variations in the often overlooked H2A C-terminal tails had significant electrostatic repercussions near the DNA entry and exit sites. The H2A N-terminal tail exerts attractive electrostatic forces towards the histone core in positions where Polymerase II halts its progress. We validate our results with comparisons to previous experimental and computational observations.
Salt-Induced Conformation and Interaction Changes of Nucleosome Core Particles
Biophysical Journal, 2002
Small angle x-ray scattering was used to follow changes in the conformation and interactions of nucleosome core particles (NCP) as a function of the monovalent salt concentration C s . The maximal extension (D max ) of the NCP (145 Ϯ 3-bp DNA) increases from 137 Ϯ 5 Å to 165 Ϯ 5 Å when C s rises from 10 to 50 mM and remains constant with further increases of C s up to 200 mM. In view of the very weak increase of the R g value in the same C s range, we attribute this D max variation to tail extension, a proposal confirmed by simulations of the entire I(q) curves, considering an ideal solution of particles with tails either condensed or extended. This tail extension is observed at higher salt values when particles contain longer DNA fragments (165 Ϯ 10 bp). The maximal extension of the tails always coincides with the screening of repulsive interactions between particles. The second virial coefficient becomes smaller than the hard sphere virial coefficient and eventually becomes negative (net attractive interactions) for NCP 145 . Addition of salt simultaneously screens Coulombic repulsive interactions between NCP and Coulombic attractive interactions between tails and DNA inside the NCP. We discuss how the coupling of these two phenomena may be of biological relevance.