Facilitated search of proteins on DNA: correlations are important

A starting point of many biological processes is protein binding to specific regions on DNA. Although typical concentrations of DNA-binding proteins are low, and target sites are typically buried among huge number of non-specific sites, the search process is frequently achieved at a remarkably fast rate. For some proteins it has been confirmed that association rates might be even larger than the maximal allowed three-dimensional diffusion rates. The current theoretical view of this phenomenon is based on the idea of lowering dimensionality, i.e., the overall search process is viewed as a combination of uncorrelated three-dimensional excursions in the solution and one-dimensional hoppings on DNA. However, some predictions of this theoretical picture contradict recent single-molecule measurements of protein diffusion processes. An alternative theoretical approach points out the importance of correlations during the search process that appear due to non-specific interactions between protein and DNA molecules. To test different theoretical ideas we performed extensive lattice Monte Carlo computer simulations of the facilitated diffusion. Our results revealed that correlations are important, and the acceleration in the search could only be achieved at some intermediate non-specific binding energies and protein concentrations. Physico-chemical aspects and the origins of these correlations are discussed.