To carry out gene transcription or silencing, transcription factors (TFs) navigate the genome to find a target site where they promote or block the recruitment of other proteins and enzymes. In the widely accepted “facilitated diffusion on the DNA” model, TFs bind DNA during diffusion with a relatively weaker affinity (nonspecific binding) than at the target site (specific binding). Although nonspecific binding allows TFs to slide or hop along the length of DNA efficiently in search of target sites, specific binding provides stability to the DNA-TF complex to carry out further recruitment of proteins and enzymes. The two different binding modes of TFs have been studied rigorously, and it has been proposed that TFs adopt two distinct conformations for two different binding affinities—one in the search mode and one in the target site–recognition mode.

Conformational change in proteins refers to alterations in the three-dimensional structure of a protein molecule. Proteins are dynamic entities, and their functions often depend on their ability to change shape. Conformational changes can be induced by various factors such as temperature, pH, and the binding of other molecules. These structural modifications are crucial for proteins to carry out their biological roles, such as binding to other molecules, catalyzing reactions, and transmitting signals within cells. There are abundant examples of such large-scale conformational changes measured in multiple TFs in the literature. In a recent study, Jin Yu and co-workers have shown the structural dynamics details of diffusion of a small TF domain protein (WRKY), showing how the protein approaches a specific recognition site on DNA. By using all-atom molecular dynamics simulations, the authors have shown that protein conformational changes might not be necessary to switch between the two binding states, in stark contrast to what is believed for TFs binding to DNA.

Building upon the previous study, Jin Yu and co-workers, in the study titled “Nonspecific vs. specific DNA binding free energetics of a transcription factor domain protein,” calculated the binding free energetics of the WRKY domain protein on specific and nonspecific DNAs. The authors showed that although the protein internal conformations remain identical in both systems, reorientations of the WRKY domain on the DNA resulted in the distinguishable binding free energies corresponding to specific and nonspecific binding. The reorientation of a protein refers to a change in spatial alignment or positioning of the protein’s tertiary structure via shift, rotation, or movement with respect to the substrate, which may affect the binding affinity of the protein to the substrate. A change in the orientation of the protein is relatively less energy consuming than a change in the conformation of the protein. The authors propose that a conformational change in the protein is not always required, and proteins can achieve variations in interaction energies with the binding partner by adopting a different orientation. The study thus provides an excitingly fresh perspective to understand DNA-protein interactions.