Intracellular Facilitated Diffusion: Searchers, Crowders, and Blockers

In bacteria, regulatory proteins search for a specific DNA-binding target via "facilitated diffusion": a series of rounds of three-dimensional diffusion in the cytoplasm, and one-dimensional (1D) linear diffusion along the DNA contour. Using large scale Brownian dynamics simulations we find that each of these steps is affected differently by crowding proteins, which can either be bound to the DNA acting as a road block to the 1D diffusion, or freely diffusing in the cytoplasm. Macromolecular crowding can strongly affect mechanistic features such as the balance between three-dimensional and 1D diffusion, but leads to surprising robustness of the total search time.