Spatial Effects on the Speed and Reliability of Protein–DNA Search

Strong experimental and theoretical evidence shows that transcription factors (TFs) and other specific DNA-binding proteins find their sites using a two-mode search: alternating between three-dimensional (3D) diffusion through the cell and one-dimensional (1D) sliding along the DNA. We show that, due to the 1D component of the search process, the search time of a TF can depend on the initial position of the TF. We formalize this effect by discriminating between two types of searches: global and local. Using analytical calculations and simulations, we estimate how close a TF and binding site need to be to make a local search likely. We then use our model to interpret the wide range of experimental measurements of this parameter. We also show that local and global searches differ significantly in average search time and the variability of search time. These results lead to a number of biological implications, including suggestions of how prokaryotes achieve rapid gene regulation and the relationship between the search mechanism and noise in gene expression. Lastly, we propose a number of experiments to verify the existence and quantify the extent of spatial effects on the TF search process in prokaryotes.