Real sequence effects on the search dynamics of transcription factors on DNA

TL;DR

This study models how transcription factors locate their DNA targets, revealing that auxiliary operators and sequence-dependent state switching significantly influence search efficiency and detection times.

Contribution

It introduces a two-state model incorporating sequence-dependent interconversion rates, highlighting the role of auxiliary operators in facilitating DNA target search.

Findings

Auxiliary operators act as funnels for TFs.

Sequence dependence affects detection times.

Target detection times vary over several orders of magnitude.

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.