Quantitative models for accelerated protein dissociation from nucleosomal DNA.
Bottom Line: This reduces the rate of transcription factor binding and is a known mechanism for regulation of gene expression via chromatin structure.There are two possible explanations for such an increase in off-rate short of an active role of the nucleosome in pushing the transcription factor off the DNA: (i) for dimeric transcription factors the nucleosome can change the equilibrium between monomeric and dimeric binding or (ii) the nucleosome can change the equilibrium between specific and non-specific binding to the DNA.We explicitly model both scenarios and find that dimeric binding can explain a large increase in off-rate while the non-specific binding model cannot be reconciled with the large, experimentally observed increase.
Affiliation: Biophysics Graduate Program, The Ohio State University, Columbus, OH, USA Center for RNA Biology, The Ohio State University, Columbus, OH, USA.Show MeSH
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Mentions: The overall off-rate of LexA in the presence of a nucleosome can be calculated as the largest non-zero eigenvalue of the rate matrix of the seven state model numerically (22). In our calculation, we found that the only parameter the overall off rate is sensitive to is the free energy difference ΔΔG ≡ ΔG(nf) - ΔG(np) between the two states when LexA is fully or partially bound (Supplementary Text). For example, the concentration of LexA affects the overall off rate (k4 is not equal to zero in the presence of a nucleosome); however, we tested a number of different LexA concentrations ranging from 0 to 50 000 nM as also tested in the experiment (12) and found that the overall off-rate only changes slightly (Supplementary Text). The value of the one important parameter ΔΔG depends on the exact amount of unwrapping (nf and np) of the nucleosome which is unknown. Thus, we tested several numerical values of ΔΔG (5 to 7 kBT) in the range of reasonable amounts of unwrapping. We found that koff(nucleosome) ranges from 0.2 to 0.65 per second (Figure 2 and Supplementary Text), which is an increase by 50- to 200-fold compared to the naked DNA case.
Affiliation: Biophysics Graduate Program, The Ohio State University, Columbus, OH, USA Center for RNA Biology, The Ohio State University, Columbus, OH, USA.