DNA-binding residues and binding mode prediction with binding-mechanism concerned models

Abstract

Background: Protein-DNA interactions are essential for fundamental biological activities including DNA transcription, replication, packaging, repair and rearrangement. Proteins interacting with DNA can be classified into two categories of binding mechanisms - sequence-specific and non-specific binding. Protein-DNA specific binding provides a mechanism to recognize correct nucleotide base pairs for sequence-specific identification. Protein-DNA non-specific binding shows sequence independent interaction for accelerated targeting by interacting with DNA backbone. Both sequence-specific and non-specific binding residues contribute to their roles for interaction.

Results: The proposed framework has two stage predictors: DNA-binding residues prediction and binding mode prediction. In the first stage - DNA-binding residues prediction, the predictor for DNA specific binding residues achieves 96.45% accuracy with 50.14% sensitivity, 99.31% specificity, 81.70% precision, and 62.15% F-measure. The predictor for DNA non-specific binding residues achieves 89.14% accuracy with 53.06% sensitivity, 95.25% specificity, 65.47% precision, and 58.62% F-measure. While combining prediction results of sequence-specific and non-specific binding residues with OR operation, the predictor achieves 89.26% accuracy with 56.86% sensitivity, 95.63% specificity, 71.92% precision, and 63.51% F-measure. In the second stage, protein-DNA binding mode prediction achieves 75.83% accuracy while using support vector machine with multi-class prediction.

Conclusion: This article presents the design of a sequence based predictor aiming to identify sequence-specific and non-specific binding residues in a transcription factor with DNA binding-mechanism concerned. The protein-DNA binding mode prediction was introduced to help improve DNA-binding residues prediction. In addition, the results of this study will help with the design of binding-mechanism concerned predictors for other families of proteins interacting with DNA.

Figure 1

Sequence-specific and non-specific binding residues of PDB 2PRT:A. Residues colored by red are sequence-specific binding residues. Residues colored by blue are non-specific binding residues. Residues colored by purple are both sequence-specific and non-specific binding residues.

Figure 2

A difficult case (PDB ID 1LMB:4) of binding residue prediction, which can be enhanced with the best aligned template of correct predicted protein-DNA binding mode. Residues colored by red means false positive. Residues colored by blue means false negative. Residues colored by green means true positive. (a) Prediction of sequence-specific binding residues. (b) Prediction of non-specific binding residues. (c) Combination of sequence-specific and non-specific binding residues prediction. (d) Enhanced prediction with the best aligned template of correct protein-DNA binding mode prediction.

Figure 3

Overall framework for DNA-binding residues prediction.