Role of Macromolecular Crowding on the Intracellular Diffusion of DNA Binding Proteins

Recent experiments suggest that cellular crowding facilitates the target search dynamics of proteins on DNA, the mechanism of which is not yet known. By using large scale computer simulations, we show that two competing factors, namely the width of the depletion layer that separates the crowder cloud from the DNA molecule and the degree of protein-crowder crosstalk, act in harmony to affect the target search dynamics of proteins. The impacts vary from nonspecific to specific target search regime. During a nonspecific search, dynamics of a protein is only minimally affected, whereas, a significantly different behaviour is observed when the protein starts forming a specific protein-DNA complex. We also find that the severity of impacts largely depends upon physiological crowder concentration and deviation from it leads to attenuation in the binding kinetics. Based on extensive kinetic study and binding energy landscape analysis, we further present a comprehensive molecular description of the search process that allows us to interpret the experimental findings.