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WIREs Comput Mol Sci
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Atomistic simulations of nucleosomes

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Abstract Nearly a dozen all‐atom molecular dynamics (MD) simulations of the nucleosome have been performed. Collectively, these simulations provide insights into the structure and dynamics of the biomolecular complex that serves as the fundamental folding unit of chromatin. Nucleosomes contain 146 base pairs of DNA wrapped in a left‐handed superhelix around a core of eight histones. This review provides a survey of what has been learned about DNA, histones, and solvent interactions based on all‐atom MD studies of the nucleosome. The longest simulations to date are on the order of 100 nanoseconds. On this time scale, nucleosomes are quite stable. DNA kinks, the histone tails, solvent, and ions are highly dynamic and can be readily investigated using equilibrium dynamics methods. Steered MD is required to observe large‐scale structural changes. The need for explicit solvent techniques is underscored by the inability of continuum solvent methods to properly describe the ion‐nucleosome radial distribution functions. The atomistic techniques reviewed here are deemed necessary for exploration of the near infinite variations in atomic composition that exists even in the canonical nucleosome octamer. Continued development of these nascent simulation efforts will enable experimentalists to utilize rational design strategies in their efforts to investigate nucleosomes and chromatin. © 2013 John Wiley & Sons, Ltd. This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods

Structure of the nucleosome (1kx5). (a) Front view of half of the nucleosome with locations of the (H3–H4)2 tetramer and H2A–H2B dimer. The four histone dimers H3, H4, H2A, and H2B are colored in blue, green, yellow, and red, respectively. The four histone dimers are arranged about a twofold dyad symmetry axis, which also intersects the middle of the DNA fragment. (b) Side view of the nucleosome with the dyad axis. (c) Temperature factor of the nucleosome showing that DNA is more mobile than histone fold domains during atomic simulations.13

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Three dimensional distribution of (a) Na+ ion and (b) water density around nucleosome.11 The images demonstrate that DNA, including the major and minor grooves, and the void in the histone core are both readily accessible to solvent. See main text for additional information. Reproduced with permission from Ref 11. Copyright 2009, American Chemical Society.

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Aufbau of nucleosomal DNA. The Aufbau of nucleosomal DNA elucidating the effect of nucleosomal DNA conformation, histone volume, dielectric, and partial charges on counterion condensation in a step by step assembly process.11 γ equals the residual DNA charge at a distance of 1 nm from the DNA surface with γ = 0 indicating complete neutralization. The proposed model demonstrates that superhelix formation by itself yields the single greatest contribution to DNA neutralization in the nucleosome and that nucleosomal DNA is more neutralized than free DNA. See main text for additional information. Reproduced with permission from Ref 11. Copyright 2009, American Chemical Society.

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DNA helical parameters extracted from simulations of 21 nucleosomes. Each plot represents one of the 12 helical parameters listed in the main text as a function of base pair position and contains 21 solid lines, one for each simulation. Rotations are plotted in degrees and translations are plotted in Å. Each plot is centered about the average value observed during MD simulations of DNA free in solution, and red lines indicate one standard deviation from the average.38 Any helical parameter value between the dotted lines should be considered readily accessible by thermal motion of DNA free in solution. The 21 nucleosomes were formed by threading a 167 base pair long segment of DNA onto the histone core.22 Each was subjected to 20 nanoseconds of simulation. Mean helical parameter values were obtained for each simulation from 1000 equally spaced conformations extracted from the last nanosecond of simulation. Each data set was then Fourier filtered to include only the wave numbers that are necessary and sufficient for superhelix formation.33 It is clear that some helix parameter values are highly conserved while others are not. Most values are within the range of thermal motion of free DNA.

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The free energy cycle displayed above provides a connection between experiment and the MD simulations presented here. In practice, the free energies for this system cannot be accurately determined from simulation.

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