Abstract
DNA–protein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNA–protein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNA–protein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNA–protein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNA–protein interaction modes exhibit some similarity to specific DNA–protein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Cα deviation from native is up to 5 Å from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNA–protein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein.
Highlights
DNA-binding proteins play an essential role in many fundamental biological activities, including DNA transcription, replication, packaging, repair and rearrangement
This paper describes a computational modeling study on nonspecific DNA–protein complexes and comparative analysis with respect to specific DNA–protein complexes
The study found that the specific DNA-binding sites on a protein are typically favorable for nonspecific DNA and that nonspecific and specific DNA–protein interaction modes are quite similar
Summary
DNA-binding proteins play an essential role in many fundamental biological activities, including DNA transcription, replication, packaging, repair and rearrangement Interactions relevant to these activities typically involve specific binding sites on both proteins and DNA. Over the past several decades, many efforts have been made in order to understand basic principles that determine the specific DNA-protein interactions. It is well-known that there does not exist a simple recognition code between protein amino acids and DNA base pairs [1,2,3,4]. An implementation of the algorithm, FTDOCK, was applied to DNA-protein docking [5], with encouraging benchmark results reported on modeling eight DNA/repressor complexes starting from unbound protein structures and canonical B-DNA. Excellent docking models were obtained for three examples by HADDOCK
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