TMB Library of Nucleosome Simulations

Sun, Ran; Li, Zilong; Bishop, Thomas C.

doi:10.1021/acs.jcim.9b00252

Cited by 13 publications

(8 citation statements)

References 54 publications

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“…We first studied the dynamics of three nucleosomes, two with natural DNA sequences proposed to be bound by Oct4 during cellular reprogramming to pluripotency ( 4 ) and one with a strong positioning sequence and no TF binding site. Whereas the dynamics of artificial nucleosomes have been previously studied with atomistic simulations ( 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ), the sequence dependence of these dynamics has not been explored. We found significant differences between the dynamics of the three nucleosomes, with the nucleosome with the most TF binding sites showing the largest amplitude of breathing and twisting motions.…”

Section: Discussionmentioning

confidence: 99%

“…By solving Newton’s equations of motion, the motions and interactions of biomolecules at atomic resolution can be studied. Nucleosome dynamics have been simulated ( 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ), and motions such as the opening and closing of the linker DNA (L-DNA) in tail-less nucleosomes ( 24 ), the twisting involved in nucleosome repositioning ( 19 ), and the behavior of the L-DNAs in the presence of linker histones ( 25 ) have been described.…”

Section: Introductionmentioning

confidence: 99%

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Nucleosomal DNA Dynamics Mediate Oct4 Pioneer Factor Binding

Huertas

MacCarthy

Schöler

et al. 2020

Biophysical Journal

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Transcription factor (TF) proteins bind to DNA to regulate gene expression. Normally, accessibility to DNA is required for their function. However, in the nucleus, the DNA is often inaccessible, wrapped around histone proteins in nucleosomes forming the chromatin. Pioneer TFs are thought to induce chromatin opening by recognizing their DNA binding sites on nucleosomes. For example, Oct4, a master regulator and inducer of stem cell pluripotency, binds to DNA in nucleosomes in a sequence-specific manner. Here, we reveal the structural dynamics of nucleosomes that mediate Oct4 binding from molecular dynamics simulations. Nucleosome flexibility and the amplitude of nucleosome motions such as breathing and twisting are enhanced in nucleosomes with multiple TF binding sites. Moreover, the regions around the binding sites display higher local structural flexibility. Probing different structures of Oct4-nucleosome complexes, we show that alternative configurations in which Oct4 recognizes partial binding sites display stable TF-DNA interactions similar to those observed in complexes with free DNA and compatible with the DNA curvature and DNA-histone interactions. Therefore, we propose a structural basis for nucleosome recognition by a pioneer TF that is essential for understanding how chromatin is unraveled during cell fate conversions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nucleosomal DNA Dynamics Mediate Oct4 Pioneer Factor Binding

Huertas

MacCarthy

Schöler

et al. 2020

Biophysical Journal

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“…There have been very few native genomic DNA sequences used in experimental and computational studies of nucleosomes 52 . Here, we constructed a structural model of a nucleosome with the DNA sequence from a well-known oncogene, KRAS .…”

Section: Methodsmentioning

confidence: 99%

Binding of regulatory proteins to nucleosomes is modulated by dynamic histone tails

Peng

Onufriev

et al. 2021

Nat Commun

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Little is known about the roles of histone tails in modulating nucleosomal DNA accessibility and its recognition by other macromolecules. Here we generate extensive atomic level conformational ensembles of histone tails in the context of the full nucleosome, totaling 65 microseconds of molecular dynamics simulations. We observe rapid conformational transitions between tail bound and unbound states, and characterize kinetic and thermodynamic properties of histone tail-DNA interactions. Different histone types exhibit distinct binding modes to specific DNA regions. Using a comprehensive set of experimental nucleosome complexes, we find that the majority of them target mutually exclusive regions with histone tails on nucleosomal/linker DNA around the super-helical locations ± 1, ± 2, and ± 7, and histone tails H3 and H4 contribute most to this process. These findings are explained within competitive binding and tail displacement models. Finally, we demonstrate the crosstalk between different histone tail post-translational modifications and mutations; those which change charge, suppress tail-DNA interactions and enhance histone tail dynamics and DNA accessibility.

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“…One of the powerful tools for studying the structure and dynamics of nucleosomes is the molecular dynamics (MD) method, which makes it possible to interpret and supplement the results of experimental studies. MD simulations have been applied to study the structure and dynamics of nucleosomal DNA [39], nucleosomal unfolding [3,12,18,44], functions and dynamics of histone tails [9,11,15,32,36,41], the role of histone post-translational modifications [14,35], DNA-DNA and DNA-protein interactions [46], counterion distribution around nucleosomes [30], role of DNA sequence in nucleosome dynamics [42], etc. However, a detailed analysis of the ionic environment of the nucleosome and the dependence of the nucleosomal structure and dynamics on it has not been previously carried out.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Ion Atmosphere Around Nucleosomes Using Supercomputer MD Simulations

2022

JSFI

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The nucleosome is the basic unit of eukaryotic DNA compaction. It consists of about 147 base pairs wrapped around an octamer of histone proteins. Nucleosomal dynamics provides the availability of packaged DNA for various factors that carry out the vital processes associated with chromatin. It is not completely known how the structure and dynamics of the nucleosome depends on the ionic environment. The current researches do not give an unambiguous answer and often contradict each other. In this paper, we demonstrate supercomputer molecular dynamics simulations of nucleosome models surrounded by monovalent sodium and potassium cations. Analyzing the trajectories, we have shown the details of the distribution of sodium and potassium ions around the linker DNA, nucleosomal DNA at the sites of nucleosomal opening, and histone residues involved in the process of nucleosomal breathing. We have demonstrated the mobility of DNA linkers and the process of nucleosomal unwrapping in various ionic environments, and also assessed the probable mechanisms of the dependence of nucleosome unwrapping on the type of ions in the system. Our study is intended to emphasize the importance of understanding the role of the ionic environment in the functioning of chromatin.

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TMB Library of Nucleosome Simulations

Cited by 13 publications

References 54 publications

Nucleosomal DNA Dynamics Mediate Oct4 Pioneer Factor Binding

Nucleosomal DNA Dynamics Mediate Oct4 Pioneer Factor Binding

Binding of regulatory proteins to nucleosomes is modulated by dynamic histone tails

Analysis of Ion Atmosphere Around Nucleosomes Using Supercomputer MD Simulations

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