A knowledge-based orientation potential for transcription factor-DNA docking

Motivation: Computational modeling of protein-DNA complexes remains a challenging problem in structural bioinformatics. One of the key factors for a successful protein-DNA docking is a potential function that can accurately discriminate the near-native structures from decoy complexes and at the same time make conformational sampling more efficient. Here, we developed a novel orientation-dependent, knowledge-based, residue-level potential for improving transcription factor (TF)-DNA docking. Results: We demonstrated the performance of this new potential in TF-DNA binding affinity prediction, discrimination of native protein-DNA complex from decoy structures, and most importantly in rigid TF-DNA docking. The rigid TF-DNA docking with the new orientation potential, on a benchmark of 38 complexes, successfully predicts 42% of the cases with root mean square deviations lower than 1 angstrom and 55% of the cases with root mean square deviations lower than 3 angstrom. The results suggest that docking with this new orientation-dependent, coarse-grained statistical potential can achieve high-docking accuracy and can serve as a crucial first step in multi-stage flexible protein-DNA docking.