Abstract
Despite their limited resolution, coarse-grained simulations have been the chosen method to obtain mechanistic information regarding the process of protein binding to DNA. Here, we demonstrate that state-of-the-art atomic simulations can capture binding events and provide new molecular insight. By using the bacterial model protein HU, we link existing crystal structures to the search and recognition states. We find that weak contacts mediated by only a few positively charged residues enable initial binding, followed by facilitated diffusion and transient rolling on DNA. Extended arms in the HU structure serve as antennae to search for DNA, permitting intrasegmental hops and intersegmental jumps. The transition to specific binding only occurs at the DNA target site, helped by its bendability, indicating a "concerted" binding mechanism between the protein and DNA. We observe a lack of direct binding to the most positively charged area, which is hidden behind HU's arms and defines the recognition state. This prevents the protein from being trapped in random DNA. Instead, the multistep binding process found here ensures that the high-affinity complex only occurs at the target position. We anticipate that other DNA-binding proteins with multiple surface-charged regions and DNA-bend induction capability might follow a similar strategy.