Asymmetric DNA-search dynamics by symmetric dimeric proteins

We focus on dimeric DNA-binding proteins from two well-studied families: orthodox type II restriction endonucleases (REs) and transcription factors (TFs). Interactions of the protein's recognition sites with the DNA and, particularly, the contribution of each of the monomers to one-dimensional (1D) sliding along nonspecific DNA were studied using computational tools. Coarse-grained molecular dynamics simulations of DNA scanning by various TFs and REs provide insights into how the symmetry of a homodimer can be broken while they nonspecifically interact with DNA. The characteristics of protein sliding along DNA, such as the average sliding length, partitioning between 1D and 3D search, and the one-dimensional diffusion coefficient D₁, strongly depend on the salt concentration, which in turn affects the probability of the two monomers adopting a cooperative symmetric sliding mechanism. Indeed, we demonstrate that maximal DNA search efficiency is achieved when the protein adopts an asymmetric search mode in which one monomer slides while its partner hops. We find that proteins classified as TFs have a higher affinity for the DNA, longer sliding lengths, and an increased probability of symmetric sliding in comparison with REs. Moreover, TFs can perform their biological function over a much wider range of salt concentrations than REs. Our results demonstrate that the different biological functions of DNA-binding proteins are related to the different nonspecific DNA search mechanisms they adopt.