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Abstract
While nucleosome positioning on eukaryotic genome play important roles for genetic regulation, molecular mechanisms of nucleosome positioning and sliding along DNA are not well understood. Here we investigated thermally-activated spontaneous nucleosome sliding mechanisms developing and applying a coarse-grained molecular simulation method that incorporates both long-range electrostatic and short-range hydrogen-bond interactions between histone octamer and DNA. The simulations revealed two distinct sliding modes depending on the nucleosomal DNA sequence. A uniform DNA sequence showed frequent sliding with one base pair step in a rotation-coupled manner, akin to screw-like motions. On the contrary, a strong positioning sequence, the so-called 601 sequence, exhibits rare, abrupt transitions of five and ten base pair steps without rotation. Moreover, we evaluated the importance of hydrogen bond interactions on the sliding mode, finding that strong and weak bonds favor respectively the rotation-coupled and -uncoupled sliding movements.
Highlights
Nucleosomes are the fundamental structural unit of eukaryotic chromatin, composed of approximately 147 base pairs of double stranded DNA wrapped around a histone octamer [1]
The highly-bent nucleosomal DNA is stabilized by a strong electrostatic attraction with histones and by more local interactions primarily via a network of hydrogen bonds to the histone octamer core residues [42]
We provided two movies showing the structure of polyCG and 601 nucleosomes during repositioning events, where the base pairs with the same indexes as the TA motifs in bold in Table 1 are represented with red spheres
Summary
Nucleosomes are the fundamental structural unit of eukaryotic chromatin, composed of approximately 147 base pairs (bp) of double stranded DNA wrapped around a histone octamer [1]. Because of the tight association with histones, nucleosomal DNA cannot be usually accessed by other proteins, inhibiting transcription factor association and gene expression [3,4]. Protein binding to a DNA region originally part of a nucleosome usually requires either complete nucleosome disassembly [5] or nucleosome sliding [6] away from the target sequence. The latter mechanism does not involve the complete breakage of histone-DNA contacts. In the complex cell environment many other factors will determine nucleosome positions. It has been suggested that remodelers may be important to enhance structural fluctuations, enabling a rapid search of the optimal nucleosome positions [8]
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