Molecular Mechanism of the Intercalation of the SOX-4 Protein into DNA Inducing Bends and Kinks.

DNA-protein interactions regulate several biophysical functions, yet the mechanism of only a few is investigated in molecular detail. An important example is the intercalation of transcription factor proteins into DNA that produce bent and kinked DNA. Here, we have studied the molecular mechanism of the intercalation of a transcription factor SOX4 into DNA with a goal to understand the sequence of molecular events that precede the bending and kinking of the DNA. Our long well-tempered metadynamics and molecular dynamics (MD) simulations show that the protein primarily binds to the backbone of DNA and rotates around it to form an intercalative native state. We show that although there are multiple pathways for intercalation, the deintercalation pathway matches with the most probable intercalation pathway. In both cases, bending and kinking happen simultaneously, driven by the onset of the intercalation of the amino acid.