Predicting interactions of winged-helix transcription factors with DNA

Determining protein-DNA interactions is important for understanding gene regulation, DNA repair and chromatin structure. Unfortunately, the structures of DNA-bound complexes are often difficult to obtain experimentally, so the development of computational methods that provide good models of these complexes would be valuable. Here, we present a rigid-body docking approach using the computer program DOT. DOT performs a complete, six-dimensional search of all orientations for two rigid molecules and calculates the interaction energy as the sum of electrostatic and van der Waals terms. DOT was applied to three winged-helix transcription factors that share similar DNA-binding structural motifs but bind DNA in different ways. Docking with linear B-form DNA models accomplished several objectives; it (1) distinguished the different ways the transcription factors bind DNA, (2) identified each protein's DNA-binding site and the DNA orientation at the site and (3) gave at least one solution among the three best-ranked that shows the protein side chain-DNA base interactions responsible for recognition. Furthermore, the ensemble of top-ranked, docked linear B-DNA fragments indicated the DNA bending induced upon protein binding. Docking linear B-DNA to structures of the transcription factor FadR suggests that the allosteric, conformational change induced upon effector binding results in loss of the ability to bend DNA as well as loss of sequence-specific interactions with DNA. The electrostatic energy term calculated by DOT is comparable to the electrostatic binding energy calculated by Poisson-Boltzmann methods. Our results show rigid-body docking that includes a rigorous treatment of the electrostatic interaction energy can be effective in predicting protein-DNA interactions.