Computer Simulation of the 30-Nanometer Chromatin Fiber

Wedemann, Gero; Langowski, Jörg

doi:10.1016/s0006-3495(02)75627-0

Cited by 161 publications

(196 citation statements)

References 39 publications

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“…Thus, in the absence of imposed stretching forces, the fiber condensation at high salt concentration was induced by adjustment of a parameter, the decrease of the effective nucleosome diameter. In the study of chromatin folding by Langowski's group, the internucleosome interaction was described by a Gay-Berne potential, a generalization of Lennard-Jones potential for objects with ellipsoidal symmetry (34). However, their focus was on modeling chromatin at near-physiological ionic conditions; thus the effects of the ionic strength on the nucleosomal interactions and on the geometrical parameters were not modeled; it was suggested that reparameterizing the Gay-Berne potential according to the experimental salt-dependence of the linear mass density of the chromatin fiber is required to explore salt-dependent behavior.…”

Section: Discussionmentioning

confidence: 99%

“…Because of the size and complexity of chromatin, computational studies have been based on coarse-grained models (29,(31)(32)(33)(34). For example, a dinucleosome was simulated on nucleosome-constrained circular DNA (31); strings of 4-24 nucleosomes were modeled by virtual bonds, and their structures were determined by geometric parameters (32); the nucleosome was represented by a spherical bead and the interaction between nucleosomes was modeled by a simple spherical isotropic steplike potential (29).…”

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confidence: 99%

“…For example, a dinucleosome was simulated on nucleosome-constrained circular DNA (31); strings of 4-24 nucleosomes were modeled by virtual bonds, and their structures were determined by geometric parameters (32); the nucleosome was represented by a spherical bead and the interaction between nucleosomes was modeled by a simple spherical isotropic steplike potential (29). A more realistic model considered nucleosomes as oblate ellipsoids, with internucleosome interactions described by the anisotropic Gay-Berne potential (34). Another approach (33) uses the Discrete Surface Charge Optimization (DiSCO) representation of the nucleosome (35).…”

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confidence: 99%

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Electrostatic mechanism of nucleosomal array folding revealed by computer simulation

Sun

Zhang

Schlick

2005

Proc. Natl. Acad. Sci. U.S.A.

109

113

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Although numerous experiments indicate that the chromatin fiber displays salt-dependent conformations, the associated molecular mechanism remains unclear. Here, we apply an irregular Discrete Surface Charge Optimization (DiSCO) model of the nucleosome with all histone tails incorporated to describe by Monte Carlo simulations salt-dependent rearrangements of a nucleosomal array with 12 nucleosomes. The ensemble of nucleosomal array conformations display salt-dependent condensation in good agreement with hydrodynamic measurements and suggest that the array adopts highly irregular 3D zig-zag conformations at high (physiological) salt concentrations and transitions into the extended ''beads-on-a-string'' conformation at low salt. Energy analyses indicate that the repulsion among linker DNA leads to this extended form, whereas internucleosome attraction drives the folding at high salt. The balance between these two contributions determines the salt-dependent condensation. Importantly, the internucleosome and linker DNA-nucleosome attractions require histone tails; we find that the H3 tails, in particular, are crucial for stabilizing the moderately folded fiber at physiological monovalent salt.chromatin modeling ͉ irregular 3D zig-zag ͉ Discrete Surface Charge Optimization model C hromatin folding and the dynamic interplay between chromatin structures and various cellular factors directly regulate fundamental gene expression and silencing processes (1-4). Extensive studies have probed the structural and dynamic properties of chromatin and the molecular mechanisms that determine these properties (5-8). Nonetheless, questions remain concerning how a chain of nucleosomes connected by linker DNA folds into a condensed 30-nm chromatin fiber under physiological conditions (9) and what the exact arrangements of nucleosomes in the 30-nm fiber are (6). Two principal architectures of fiber arrangement proposed are the solenoid and zig-zag models. They differ significantly in how the linker DNA is arranged within the condensed chromatin fiber. In the solenoid model, the linker DNA is bent such that the consecutive nucleosomes interact with each other and form a helix (10-14); in the zig-zag model, the linker DNA remains straight and crosses the fiber axis so that the consecutive nucleosomes appear at the opposite side of the fiber axis (5, 15-18).The structure of chromatin strongly depends on the salt environment, both in terms of the valence of the ions and their concentration in solution (1). At low salt concentrations, chromatin adopts the extended ''beads-on-a-string'' conformation, whereas at high salt concentrations it folds into compact forms. In the presence of linker histones (H1 or H5) under physiological salt conditions, chromatin forms the folded 30-nm fiber. The histone tails are known to be crucial for the folding of chromatin fibers (19-21; reviewed in ref. 22). The tail domains, accounting for Ϸ50% of the positive charges of the histone octamer, are located at the N-terminal portions of H2A, H2B, H3, and H4, and ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Electrostatic mechanism of nucleosomal array folding revealed by computer simulation

Sun

Zhang

Schlick

2005

Proc. Natl. Acad. Sci. U.S.A.

109

113

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“…Their systematic Monte Carlo simulations also support the notion that nucleosome interdigitation explains higher order chromatin structure and that the nucleosome repeat length affects the internal structure of the chromatin fiber. Other innovative modeling and simulation approaches for chromatin have explored various aspects of chromatin structure (21)(22)(23)(24)(25).…”

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confidence: 99%

Evidence for heteromorphic chromatin fibers from analysis of nucleosome interactions

Grigoryev

Arya

Correll

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

245

358

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The architecture of the chromatin fiber, which determines DNA accessibility for transcription and other template-directed biological processes, remains unknown. Here we investigate the internal organization of the 30-nm chromatin fiber, combining Monte Carlo simulations of nucleosome chain folding with EM-assisted nucleosome interaction capture (EMANIC). We show that at physiological concentrations of monovalent ions, linker histones lead to a tight 2-start zigzag dominated by interactions between alternate nucleosomes (i ؎ 2) and sealed by histone N-tails. Divalent ions further compact the fiber by promoting bending in some linker DNAs and hence raising sequential nucleosome interactions (i ؎ 1). Remarkably, both straight and bent linker DNA conformations are retained in the fully compact chromatin fiber as inferred from both EMANIC and modeling. This conformational variability is energetically favorable as it helps accommodate DNA crossings within the fiber axis. Our results thus show that the 2-start zigzag topology and the type of linker DNA bending that defines solenoid models may be simultaneously present in a structurally heteromorphic chromatin fiber with uniform 30 nm diameter. Our data also suggest that dynamic linker DNA bending by linker histones and divalent cations in vivo may mediate the transition between tight nucleosome packing within discrete 30-nm fibers and self-associated higher-order chromosomal forms.chromatin structure ͉ electron microscopy ͉ mesoscopic modeling ͉ Monte Carlo simulations ͉ linker histone T he DNA in eukaryotic chromatin is packed and functionally regulated by histones and nonhistone architectural proteins (1). The primary packing level is represented by an array of repeating units, the nucleosomes, where the DNA is wound around histone octamers (2). Further compaction is achieved through a hierarchy of folding levels, including the 30-nm chromatin fiber (secondary level) and more compact and self-associating tertiary and quaternary forms whose structures are unknown (3-6). Because DNA conformation in chromatin and nucleosome packing are intimately connected to DNA/protein recognition and gene regulation, there has been intense interest in understanding chromatin structure, energetics, and dynamics. Some experimental studies have suggested that nucleosomal arrays fold in a zigzag arrangement with relatively straight linkers and a 2-start nucleosome interaction pattern that brings each nucleosome in proximity to its second nearest neighbor (7-10) consistent with chromatin fibers observed in situ (11). Other evidence suggests that chromatin condensed with linker histones and divalent cations such as Mg 2ϩ can form either zigzag structures with various nucleosome topologies (12, 13) or solenoid-like arrangements. The latter class of structures has bent DNA linkers and predominant interactions between either nearest neighbor nucleosomes (14, 15) and/or between every fifth or sixth nucleosome along the chain (16,17).The picture has became more complex recently with our heighte...

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“…Hence modeling fiber structure and motion requires specialized models that treat the system's electrostatics as accurately as possible -since these features are thought to be crucial for chromatin organization -while approximating others so as to make possible studies of nucleosome arrays (or oligonucleosomes) with sufficient configurational sampling (e.g., 100 million configurations) or simulation times of milliseconds and longer to be biologically relevant. In recent years, a variety of computational models have been developed (e.g., [22,23,24,25,26,27,28]). …”

Section: Chromatin Structurementioning

confidence: 99%

From Macroscopic to Mesoscopic Models of Chromatin Folding

Schlick¹

2009

Multiscale Methods

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An overview of the evolution of computer models for simulation of chromatin folding is presented. Chromatin is the protein/nucleic acid fiber that stores the genetic material in higher organisms. Many biological questions concerning the fiber structure and its dependence on internal and external factors remain a puzzle. Modeling and simulation can in theory provide molecular view for analysis, but the sheer size and range of spatial and temporal scales involved require tailored multiscale models. Our first-generation, macroscopic models ignored histone tail flexibility but generated insights into preferred zigzag configurations and folding/unfolding dynamics at univalent salt. The second-generation mesoscale models incorporated histone tail flexibility, linker histones, and the presence of divalent ions. Recent results reveal the profound compaction induced by linker histones and the polymorphic fiber structure at divalent salt environments, with a small fraction of the linker DNAs bent rather than straight for ultimate compaction. Our chromatin model can be extended further to study many important questions dealing with histone tail post-translational modifications, the effects of variations in linker DNA length and of histone variants on chromatin structure, and the nature of higher-order fiber structures. IntroductionOne of the current challenges in scientific computing is model development that entails bridging the resolution among different spatial and temporal scales. In biological applications, a wide range of spatial scales defines systems, from the quantum particles to atomic, molecular, cellular, organ, system and genome entities. Temporal scales range from sub-femtosecond for electronic motion to billions of years of evolutionary changes. As our computing power and algorithms have improved, problems of greater scientific significance can be addressed with enhanced confidence and accuracy. However, developing appropriate molecular models and simulation algorithms to answer specific biological questions that require bridging all-atom details with the macroscopic view of activity on the cellular level remains an ad-hoc endeavor which requires as much art as science.As a special volume of SIAM's journal on Multiscale Modeling and Simulation illustrated [1], multiscale biology is being developed by many varied techniques and applied to a variety of problems, such as involving protein and RNA threedimensional structures, DNA supercoiling, ribosomal motions, DNA packaging in viruses, heart muscle motion, RNA translation, or fruit fly circadian rhythm. For these applications, techniques involve hierarchical methods that transform fast, low-resolution to slower, higher-resolution models; dynamics propagation using projection of standard molecular dynamics to longer timescales using master-equation methods; rigid-body dynamics; elastic or normal-mode models; and coarse-grained studies of slow, large-scale motions and features using differential equations for global properties or statistical methods.Thi...

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Computer Simulation of the 30-Nanometer Chromatin Fiber

Cited by 161 publications

References 39 publications

Electrostatic mechanism of nucleosomal array folding revealed by computer simulation

Electrostatic mechanism of nucleosomal array folding revealed by computer simulation

Evidence for heteromorphic chromatin fibers from analysis of nucleosome interactions

From Macroscopic to Mesoscopic Models of Chromatin Folding

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