One of the most critical aspects of protein functioning in cells is the ability of protein molecules to quickly find and recognize specific targets on DNA. Kinetic measurements indicate that in many cases the corresponding association rates are surprisingly large. For some proteins they might be even larger than maximal allowed 3D diffusion rates, and these observations stimulated strong debates about possible mechanisms. Current experimental and theoretical studies suggest that the search process is a complex combination of 3D and 1D motions. Although significant progress in understanding protein search and recognition of targets on DNA has been achieved, detailed mechanisms of these processes are still not well understood. The most surprising observation is that proteins spend most of the search time being non-specifically bound on DNA where they supposedly move very slowly, but still the overall search is very fast. Another intriguing result is known as a speed-selectivity paradox. It suggests that experimentally observed fast findings of targets require smooth protein-DNA binding potentials, while the stability of the specific protein-DNA complex imposes a large energy gap which should significantly slow down the protein molecule. Here we propose a possible mechanism that might explain fast protein search for targets on DNA. We developed a discrete-state stochastic framework that allowed us to investigate explicitly target search phenomena. Using exact calculations by analyzing first passage distributions, it is shown that strong coupling between 3D and 1D motion might accelerate the search. It is argued that the speed-selectivity paradox does not exist since it is an artifact of the continuum approximation. We also show how our method can be utilized for taking into account the inter-segment processes. This is important to explain large deviations from the diffusion limit. Our theoretical analysis is supported by Monte Carlo computer simulations and it agrees with all available experimental observations. Physical-chemical aspects of the mechanism are also discussed.
View profile of Anatoly Kolomeisky.