A theoretical study of the role of bulk crowders on target search dynamics of DNA binding proteins

One of the major challenges posed by DNA-binding proteins to locate and bind their target sequences is the in vivo cellular environment, which is densely crowded by the high concentrations of other proteins and macromolecules that may hinder the diffusion of a protein molecule searching for its binding site on the DNA. To explore the molecular crowding effect on the target search, in this study we develop a theoretical method based on a discrete-state stochastic framework to explicitly investigate the role of bulk crowding in the cellular environment during the protein search. It is found that based on the spatial positions of the target and the crowders, and the size of the crowders, the protein search dynamics can accelerate or slow down and this is discussed here using physical explanations. When the bulk crowders block the target site, the crowding effect is the strongest. The search time, in this case, increases for 3D search pathways, while the effect of bulk crowding is minimal for 1D search pathways. These theoretical results are also tested using extensive Monte Carlo computer simulations. All these results provide a deeper understanding of the role of facilitated diffusion in in vivo target search dynamics. (paper)