Flexible Histone Tails in a New Mesoscopic Oligonucleosome Model (original) (raw)
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Role of histone tails in chromatin folding revealed by a mesoscopic oligonucleosome model
Proceedings of the National Academy of Sciences, 2006
The role of each histone tail in regulating chromatin structure is elucidated by using a coarse-grained model of an oligonucleosome incorporating flexible histone tails that reproduces the conformational and dynamical properties of chromatin. Specifically, a tailored configurational-bias Monte Carlo method that efficiently samples the possible conformational states of oligonucleosomes yields positional distributions of histone tails around nucleosomes and illuminates the nature of tail͞core͞DNA interactions at various salt milieus. Analyses indicate that the H4 histone tails are most important in terms of mediating internucleosomal interactions, especially in highly compact chromatin with linker histones, followed by H3, H2A, and H2B tails in decreasing order of importance. In addition to mediating internucleosomal interactions, the H3 histone tails crucially screen the electrostatic repulsion between the entering͞exiting DNA linkers. The H2A and H2B tails distribute themselves along the periphery of chromatin fibers and are important for mediating fiber͞fiber interactions. A delicate balance between tail-mediated internucleosomal attraction and repulsion among linker DNAs allows the entering͞exiting linker DNAs to align perpendicular to each other in linker-histone deficient chromatin, leading to the formation of an irregular zigzag-folded fiber with dominant pair-wise interactions between nucleosomes i and i ؎ 4.
Nucleic Acids Research, 2012
Monte Carlo simulations of a mesoscale model of oligonucleosomes are analyzed to examine the role of dynamic-linker histone (LH) binding/unbinding in high monovalent salt with divalent ions, and to further interpret noted chromatin fiber softening by dynamic LH in monovalent salt conditions. We find that divalent ions produce a fiber stiffening effect that competes with, but does not overshadow, the dramatic softening triggered by dynamic-LH behavior. Indeed, we find that in typical in vivo conditions, dynamic-LH binding/unbinding reduces fiber stiffening dramatically (by a factor of almost 5, as measured by the elasticity modulus) compared with rigidly fixed LH, and also the force needed to initiate chromatin unfolding, making it consistent with those of molecular motors. Our data also show that, during unfolding, divalent ions together with LHs induce linker-DNA bending and DNA-DNA repulsion screening, which guarantee formation of heteromorphic superbeads-on-a-string structures that combine regions of loose and compact fiber independently of the characteristics of the LH-core bond. These structures might be important for gene regulation as they expose regions of the DNA selectively. Dynamic control of LH binding/unbinding, either globally or locally, in the presence of divalent ions, might constitute a mechanism for regulation of gene expression.
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.
Biophysical Journal, 2009
Coarse-grained Langevin molecular dynamics computer simulations were conducted for systems that mimic solutions of nucleosome core particles (NCPs). The NCP was modeled as a negatively charged spherical particle representing the complex of DNA and the globular part of the histones combined with attached strings of connected charged beads modeling the histone tails. The size, charge, and distribution of the tails relative to the core were built to match real NCPs. Three models of NCPs were constructed to represent different extents of covalent modification on the histone tails: (nonmodified) recombinant (rNCP), acetylated (aNCP), and acetylated and phosphorylated (paNCP). The simulation cell contained 10 NCPs in a dielectric continuum with explicit mobile counterions and added salt. The NCP-NCP interaction is decisively dependent on the modification state of the histone tails and on salt conditions. Increasing the monovalent salt concentration (KCl) from salt-free to physiological concentration leads to NCP aggregation in solution for rNCP, whereas NCP associates are observed only occasionally in the system of aNCPs. In the presence of divalent salt (Mg 2þ), rNCPs form dense stable aggregates, whereas aNCPs form aggregates less frequently. Aggregates are formed via histone-tail bridging and accumulation of counterions in the regions of NCP-NCP contacts. The paNCPs do not show NCP-NCP interaction upon addition of KCl or in the presence of Mg 2þ. Simulations for systems with a gradual substitution of K þ for Mg 2þ , to mimic the Mg 2þ titration of an NCP solution, were performed. The rNCP system showed stronger aggregation that occurred at lower concentrations of added Mg 2þ , compared to the aNCP system. Additional molecular dynamics simulations performed with a single NCP in the simulation cell showed that detachment of the tails from the NCP core was modest under a wide range of salt concentrations. This implies that salt-induced tail dissociation of the histone tails from the globular NCP is not in itself a major factor in NCP-NCP aggregation. The approximation of coarse-graining, with respect to the description of the NCP as a sphere with uniform charge distribution, was tested in control simulations. A more detailed description of the NCP did not change the main features of the results. Overall, the results of this work are in agreement with experimental data reported for NCP solutions and for chromatin arrays.
Multiscale Modeling of Nucleosome Dynamics
Biophysical Journal, 2007
Nucleosomes form the fundamental building blocks of chromatin. Subtle modifications of the constituent histone tails mediate chromatin stability and regulate gene expression. For this reason, it is important to understand structural dynamics of nucleosomes at atomic levels. We report a novel multiscale model of the fundamental chromatin unit, a nucleosome, using a simplified model for rapid discrete molecular dynamics simulations and an all-atom model for detailed structural investigation. Using a simplified structural model, we perform equilibrium simulations of a single nucleosome at various temperatures. We further reconstruct all-atom nucleosome structures from simulation trajectories. We find that histone tails bind to nucleosomal DNA via strong salt-bridge interactions over a wide range of temperatures, suggesting a mechanism of chromatin structural organization whereby histone tails regulate inter-and intranucleosomal assemblies via binding with nucleosomal DNA. We identify specific regions of the histone core H2A/H2B-H4/H3-H3/H4-H2B/H2A, termed ''cold sites'', which retain a significant fraction of contacts with adjoining residues throughout the simulation, indicating their functional role in nucleosome organization. Cold sites are clustered around H3-H3, H2A-H4 and H4-H2A interhistone interfaces, indicating the necessity of these contacts for nucleosome stability. Essential dynamics analysis of simulation trajectories shows that bending across the H3-H3 is a prominent mode of intranucleosomal dynamics. We postulate that effects of salts on mononucleosomes can be modeled in discrete molecular dynamics by modulating histone-DNA interaction potentials. Local fluctuations in nucleosomal DNA vary significantly along the DNA sequence, suggesting that only a fraction of histone-DNA contacts make strong interactions dominating mononucleosomal dynamics. Our findings suggest that histone tails have a direct functional role in stabilizing higher-order chromatin structure, mediated by salt-bridge interactions with adjacent DNA.
From Macroscopic to Mesoscopic Models of Chromatin Folding
Multiscale Methods, 2009
An overview of the evolution of macroscale to mesoscale computer models for simulation of chromatin, the protein nucleic acid fiber that stores the DNA in higher organisms, is presented. Many biological questions concerning fiber structure remain a puzzle. The sheer size and range of spatial and temporal scales require tailored multiscale models. Our first-generation macroscopic models ignored histone tail flexibility but generated insights info preferred zigzag configurations and folding/unfolding dynamics. The second-generation mesoscale models incorporate histone tail flexibility, linker histones, and divalent ion effects to reveal the profound compaction induced by linker histones and the polymorphic fiber architecture at divalent salt environments, with a small fraction of the linker DNAs bent rather than straight for optimal compaction. Our chromatin model can be extended further to study many important biological questions concerning post-translational modifications, fiber di...
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...
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.
Electrostatic effect of H1-histone protein binding on nucleosome repeat length
Physical biology, 2014
Within a simple biophysical model we describe the effect of electrostatic binding of H1 histone proteins on the nucleosome repeat length in chromatin. The length of wrapped DNA optimizes its binding energy to the histone core and the elastic energy penalty of DNA wrapping. The magnitude of the effect predicted from our model is in agreement with the systematic experimental data on the linear variation of nucleosome repeat lengths with H1/nucleosome ratio (Woodcock C L et al 2006 Chromos. Res. 14 17-25). We compare our model to the data for different cell types and organisms, with a widely varying ratio of bound H1 histones per nucleosome. We underline the importance of this non-specific histone-DNA charge-balance mechanism in regulating the positioning of nucleosomes and the degree of compaction of chromatin fibers in eukaryotic cells.