How a protein searches for its site on DNA: the mechanism of facilitated diffusion

A number of vital biological processes rely on fast and precise recognition of a specific DNA sequence (site) by a protein. How can a protein find its site on a long DNA molecule among 106–109 decoy sites? Here, we present our recent studies of the protein–DNA search problem. Seminal biophysical works suggested that the protein–DNA search is facilitated by 1D diffusion of the protein along DNA (sliding). We present a simple framework to calculate the mean search time and focus on several new aspects of the process such as the roles of DNA sequence and protein conformational flexibility. We demonstrate that coupling of DNA recognition with conformational transition within the protein–DNA complex is essential for fast search. To approach the complexity of the in vivo environment, we examine how the search can proceed at realistic DNA concentrations and binding constants. We propose a new mechanism for local distance-dependent search that is likely essential in bacteria. Simulations of the search on tightly packed DNA and crowded DNA demonstrate that our theoretical framework can be extended to correctly predicts search time in such complicated environments. We relate our findings to a broad range of experiments and summarize the results of our recent single-molecule studies of a eukaryotic protein (p53) sliding along DNA.