Chromatin Folding [Sun et al., 2005; Zhang et al., 2003; Beard & Schlick, 2001a; Beard & Schlick, 2000a; Beard & Schlick, 2000b; Huang et al., 2001; Jian et al., 1998; Beard & Schlick, 2001b]

The compact form of the chromatin fiber is a critical regulator of fundamental processes such as transcription, translation and replication [Wolffe, 1998; Kornberg & Lorch, 1999]. These reactions can occur only when the fiber is unraveled and the DNA strands contained within are exposed to interact with nuclear proteins. While progress on identifying the biochemical mechanisms that control localized folding and hence govern access to genetic information continues, the internal structure of the chromatin fiber -- let alone the structural pathways for folding and unfolding -- remain unknown. Simulations can suggest geometric/topological models and test hypotheses (zigzag versus solenoid, straight versus bent linker DNA) for chromatin organization. To offer structural insights into how this nucleoprotein complex might be organized, we have performed both Monte Carlo and brownian dynamics simulations of polynucleosomes at increasing levels of sophistication.

In our early studies, we have combined our macroscopic DNA supercoiling model [Jian et al., 1998] for wormlike chains with an electrostatic and mechanical treatment [Beard & Schlick, 2001b] for the nucleosome core particle. We treat the core particles as rigid electrostatically charged disks linked via charged elastic DNA segments and surrounded by a microionic hydrodynamic solution. Each nucleosome unit is represented by several hundred charges optimized so that the effective Debye-Hückel electrostatic field matches the field predicted by the nonlinear Poisson-Boltzmann equation. On the basis of Brownian dynamics simulations, we show that oligonucleosomes condense and unfold in a salt-dependent manner analogous to the chromatin fiber. Our predicted chromatin model shows good agreement with experimental diffusion coefficients and small angle X-ray scattering data. A fiber of width 30 nm, organized in a compact helical zigzag pattern with about 4 nucleosomes per 10 nm, naturally emerges from a repeating nucleosome folding motif. This fiber has a cross sectional radius of gyration of 8.66 nm, in close agreement with corresponding values for rat thymus and chicken erythrocyte chromatin (8.82 and 8.5 nm, respectively).

At the next level of sophistication, the regular nucleosome disk of the previous studies is replaced by the rigid corrugated object shown in the figure, which is more representative of the irregular nature of nucleosome core [Zhang et al., 2003]. This model therefore properly accounts for the impact of the positively charged histone tails H3, H4, H2A, and H2B emanating from the nucleosome core on chromatin organization. The impact of salt-concentration on chromatin folding is evaluated via Monte Carlo simulations of an array of 12 nucleosomes [Sun et al., 2005]. Our simulations reveal that the nucleosomal array adops a highly irregular three-dimensional zig-zag conformation at high salt concentrations and transitions into a "beads-on-a-string" conformation at low salt concentrations, in agreement with experiments by the research groups of Chris Woodcock and Sergei Grigoryev [Woodcock et al., 1993; Bednar et al., 1998]. It is further shown that the primary driving force for chromatin unfolding at low salt concentration is the electrostatic repulsion between DNA linkers. On the other hand, chromatin folding at high salt concentration is mainly driven by electrostatic attractions between neighboring nucleosomes; our simulations suggesting that the H3 histone tails play a key role in this process.

In the above model, the histone tails have been modeled as rigid objects incapable of exploring the energy landscape around the parent nucleosome core. Our current work is aimed at developing a flexible bead-chain model of the histone tails based on the protein subunit model of the University of Houston brownian dynamics program [Briggs et al., 1995].

Our results pave the way for investigating structural/functional consequences of histone tails, DNA linker sequence, and biochemical on gene control [Hagmanm, 1999; Kornberg & Lorch, 1999].

• Article -- "Modeling Salt-Mediated Electrostatics of Macromolecules: The Discrete Surface Charge Optimization Algorithm and Its Application to the Nucleosome"
  
  
• Article -- "Computational Modeling Predicts the Structure and Dynamics of Chromatin Fiber"
  
  
• Article -- "Constructing Irregular Surfaces to Enclose Macromolecular Complexes for Mesoscale Modeling Using the Discrete Surface Charge Optimization (DiSCO) Algorithm"
  
  
• Article -- "Electrostatic Mechanism of Nucleosomal Array Floding Revealed by Computer Simulation"
  
  
• Art Gallery -- "Surface Building of DiSCO Model Based on the Macromolecule's Geometry"
  
  
• Art Gallery -- "Assignment and Optimization of the Discrete Charges on DiSCO Model's Surface"
  
  
• Gaurav Arya's Home Page
  
  
• Qing Zhang's Home Page
  
  
• Dan Beard's Home Page
  
  

Click to go back to Research