Multiscale modeling of nucleosome dynamics

Shantanu Sharma, Feng Ding, Nikolay Dokholyan

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1457-1470
Number of pages14
JournalBiophysical journal
Volume92
Issue number5
DOIs
StatePublished - Jan 1 2007

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Nucleosomes
Histones
Chromatin
DNA
Salts
Structural Models
Molecular Dynamics Simulation
Histone Code
Temperature
Gene Expression

All Science Journal Classification (ASJC) codes

  • Biophysics

Cite this

Sharma, Shantanu ; Ding, Feng ; Dokholyan, Nikolay. / Multiscale modeling of nucleosome dynamics. In: Biophysical journal. 2007 ; Vol. 92, No. 5. pp. 1457-1470.
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Multiscale modeling of nucleosome dynamics. / Sharma, Shantanu; Ding, Feng; Dokholyan, Nikolay.

In: Biophysical journal, Vol. 92, No. 5, 01.01.2007, p. 1457-1470.

Research output: Contribution to journalArticle

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