J: A threading-based method for the prediction of DNAbinding proteins with application to the human genome. PLoS Comput Biol 2009

Diverse mechanisms for DNA-protein recognition have been elucidated in numerous atomic complex structures from various protein families. These structural data provide an invaluable knowledge base not only for understanding DNA-protein interactions, but also for developing specialized methods that predict the DNA-binding function from protein structure. While such methods are useful, a major limitation is that they require an experimental structure of the target as input. To overcome this obstacle, we develop a threading-based method, DNA-Binding-Domain-Threader (DBD-Threader), for the prediction of DNA-binding domains and associated DNA-binding protein residues. Our method, which uses a template library composed of DNA-protein complex structures, requires only the target protein’s sequence. In our approach, fold similarity and DNA-binding propensity are employed as two functional discriminating properties. In benchmark tests on 179 DNA-binding and 3,797 non-DNA-binding proteins, using templates whose sequence identity is less than 30 % to the target, DBD-Threader achieves a sensitivity/precision of 56%/86%. This performance is considerably better than the standard sequence comparison method PSI-BLAST and is comparable to DBD-Hunter, which requires an experimental structure as input. Moreover, for over 70 % of predicted DNA-binding domains, the backbone Root Mean Square Deviations (RMSDs) of the top-ranked structural models are within 6.5 A ̊ of their experimental structures, with their associated DNA-binding sites identified at satisfactory accuracy. Additionally, DBD-Threader correctly assigned the SCOP superfamily fo