Abstract
Nucleosome breathing potentially increases the DNA exposure, which in turn recruits DNA-binding protein and regulates gene transcription. Numerous studies have shown the critical roles of N-terminal tails of histones H3 and H4 in gene expression; however, few studies have focused on the H2A C-terminal tail. Here we present thorough computational studies on a single nucleosome particle showing the linker DNA closing and opening, which is thought to be nucleosome breathing. With our simulation, the H2A C-terminal and H3 N-terminal tails were found to modulate the nucleosome conformation differently. The H2A C-terminal tail regulates nucleosome conformation by binding to linker DNA at different locations, whereas the H3 N-terminal tail regulates linker DNA by binding to it in different patterns. Further MD simulation on tail truncated structures corroborates this analysis. These findings replenish our understanding of the histone tail regulation mechanism on atomic level.
Highlights
Tails and nucleosome core tends to destabilize the secondary structure of the histone tails[22,23]
The histone fold domains and nucleosomal DNA showed greater variations in root mean square deviations of heavy atoms of nucleosome at 353 K than at 300 K, as expected (Fig. 2a and Supplementary Fig. S1), the rmsds reached equilibrium at least within 20 ns. This is consistent with previous studies, which suggested that the histone core proteins are relatively stable[27,35,36]
The distance between two ends of the linker DNA varied from ~0 to ~8 nm (Fig. 2a black curves, Supplementary Fig. S4), covering the range of linker DNA distances shown in previous fluorescence resonance energy transfer (FRET) studies on nucleosome breathing[16,37]
Summary
Tails and nucleosome core tends to destabilize the secondary structure of the histone tails[22,23]. To obtain as many conformational changes as possible, we performed 10 independent, 100-ns long, all-atom MD simulations at a relatively high temperature (353 K) to accelerate the dynamics In these simulations, we successfully observed the nucleosome structural changes, in which the linker DNA ends either approaching or departing each other. On closely examining the closing and opening processes, we found that H2ACtT and H3NtT play apivotal role in regulating linker DNA dynamics and nucleosome structures. In the case with both tails truncated, the nucleosome, which was initially in the closed conformation, rapidly transitioned into the open conformation
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