Inferring protein-DNA dependencies using motif alignments and mutual information

Motivation: Mutual information can be used to explore covarying positions in biological sequences. In the past, it has been successfully used to infer RNA secondary structure conformations from multiple sequence alignments. In this study, we show that the same principles allow the discovery of transcription factor amino acids that are coevolving with nucleotides in their DNA-binding targets. Results: Given an alignment of transcription factor binding domains, and a separate alignment of their DNA target motifs, we demonstrate that mutually covarying base-amino acid positions may indicate possible protein-DNA contacts. Examples explored in this study include C2H2 zinc finger, homeodomain and bHLH DNA-binding motif families, where a number of known base-amino acid contacting positions are identified. Mutual information analyses may aid the prediction of base-amino acid contacting pairs for particular transcription factor families, thereby yielding structural insights from sequence information alone. Such inference of protein-DNA contacting positions may guide future experimental studies of DNA recognition.