Abstract
Recent experiments show that transcription factors (TFs) indeed use the facilitated diffusion mechanism to locate their target sequences on DNA in living bacteria cells: TFs alternate between sliding motion along DNA and relocation events through the cytoplasm. From simulations and theoretical analysis we study the TF-sliding motion for a large section of the DNA-sequence of a common E. coli strain, based on the two-state TF-model with a fast-sliding search state and a recognition state enabling target detection. For the probability to detect the target before dissociating from DNA the TF-search times self-consistently depend heavily on whether or not an auxiliary operator (an accessible sequence similar to the main operator) is present in the genome section. Importantly, within our model the extent to which the interconversion rates between search and recognition states depend on the underlying nucleotide sequence is varied. A moderate dependence maximises the capability to distinguish between the main operator and similar sequences. Moreover, these auxiliary operators serve as starting points for DNA looping with the main operator, yielding a spectrum of target detection times spanning several orders of magnitude. Auxiliary operators are shown to act as funnels facilitating target detection by TFs.
Highlights
Theoretically[29,30,31,32,33]
We focus on base pairs 359,990 to 370,010 of E. coli strain K-12 MG1655 from ecocyc.org[43], comprising the genes lacA, lacY, and lacZ as well as the three operators O1, O2, and O3, to which the lac repressor (LacI) can bind[44]
One-dimensional sliding of a transcription factors (TFs) along the DNA is a vital ingredient of the facilitated diffusion model
Summary
Theoretically[29,30,31,32,33]. the fact that genes, that interact via local TFs, are statistically proximate along the prokaryotic genome (colocalisation) was argued to be due to the increased interaction rates (rapid search hypothesis)[34,35,36]. Motivated by recent experiments showing that on encounter the target operator is not detected with certainty by a TF sliding along the DNA15, we here combine theoretical and simulations analyses to quantify the sliding motion of a TF along the real nucleotide sequence of a common E. coli strain in the presence of crowding proteins on the DNA. We first focus on the processes in the target region carrying possible binding positions between the two nearest roadblocks to the left and to the right of the main operator O1. Such roadblocks could be proteins like H-NS or HU42. We only consider configurations in which the main operator is accessible From both TF detects simulations the target in athned caonrraepcpt roorxieimntaatteioannableyftoicrealdaipssporcoiaactihonw.eTdheeteTrFmsitnaerttshferopmrobaarbainlidtyompt that the position in this target region
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