Facilitated diffusion of proteins on DNA

The idea that non-specific DNA-binding proteins are capable of finding their cognate sites on DNA much faster than the time calculated via three-dimensional diffusion theory has been proposed in recent years as an important mechanism for the activity of DNA enzymes and transcription factors. The goal of this study was to investigate, using Brownian dynamics simulation methods, the fundamental mechanisms involved in facilitated diffusion of DNA-binding proteins near and on DNA chains, and the relative roles these mechanisms play in determining the mean time proteins require to find their specific targets on a DNA chain. Two different scenarios were investigated. In the first scenario, the DNA was an extended chain aligned on a surface with a cognate site located at one end of the DNA, exposed to a homogenous solution of proteins with attractive interactions for the DNA monomers. The dynamics of these proteins were characterized and mean time required for proteins to find their specific target DNA monomer was studied as a function of protein concentration in the bulk and the strength of the non-specific binding energy between DNA and proteins. An optimal binding energy was identified corresponding to the most efficient search process. In the second scenario, the DNA also had a coiled conformation. The effect of DNA conformation on protein transport and the mean first passage time was studied. Here, it was discovered that proteins found their target on a coiled DNA much faster that on partially extended DNA chains. The occurrence of inter-segmental transfers, where proteins moved a large distance in sequence space by short hops across loops, was confirmed and correlated with the enhanced target search efficiency observed in coiled DNA. The results of this simulation study reproduced some of the previous predictions of kinetic models and experimental observations, and extended the knowledge about the target search process of DNA-binding proteins to aspects not easily studied using available theoretical and experimental methods