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Evolutionary approach to predicting the binding site residues of a protein from its primary sequence.

ABSTRACT: Protein binding site residues, especially catalytic residues, play a central role in protein function. Because more than 99% of the ? 12 million protein sequences in the nonredundant protein database have no structural information, it is desirable to develop methods to predict the binding site residues of a protein from its primary sequence. This task is highly challenging, because the binding site residues constitute only a small portion of a protein. However, the binding site residues of a protein are clustered in its functional pocket(s), and their spatial patterns tend to be conserved in evolution. To take advantage of these evolutionary and structural principles, we constructed a database of ? 50,000 templates (called the pocket-containing segment database), each of which includes not only a sequence segment that contains a functional pocket but also the structural attributes of the pocket. To use this database, we designed a template-matching technique, termed residue-matching profiling, and established a criterion for selecting templates for a query sequence. Finally, we developed a probabilistic model for assigning spatial scores to matched residues between the template and query sequence in local alignments using a set of selected scoring matrices and for computing the binding likelihood of each matched residue in the query sequence. From the likelihoods, one can predict the binding site residues in the query sequence. An automated computational pipeline was developed for our method. A performance evaluation shows that our method achieves a 70% precision in predicting binding site residues at 60% sensitivity.

SUBMITTER: Tseng YY

PROVIDER: S-EPMC3069214 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Evolutionary approach to predicting the binding site residues of a protein from its primary sequence.

Tseng Yan Yuan YY Li Wen-Hsiung WH Li Wen-Hsiung WH

Proceedings of the National Academy of Sciences of the United States of America 20110314 13

Protein binding site residues, especially catalytic residues, play a central role in protein function. Because more than 99% of the ∼ 12 million protein sequences in the nonredundant protein database have no structural information, it is desirable to develop methods to predict the binding site residues of a protein from its primary sequence. This task is highly challenging, because the binding site residues constitute only a small portion of a protein. However, the binding site residues of a pro ...[more]

PMID: 21402946

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Project description:BackgroundThe vitamins are important cofactors in various enzymatic-reactions. In past, many inhibitors have been designed against vitamin binding pockets in order to inhibit vitamin-protein interactions. Thus, it is important to identify vitamin interacting residues in a protein. It is possible to detect vitamin-binding pockets on a protein, if its tertiary structure is known. Unfortunately tertiary structures of limited proteins are available. Therefore, it is important to develop in-silico models for predicting vitamin interacting residues in protein from its primary structure.ResultsIn this study, first we compared protein-interacting residues of vitamins with other ligands using Two Sample Logo (TSL). It was observed that ATP, GTP, NAD, FAD and mannose preferred {G,R,K,S,H}, {G,K,T,S,D,N}, {T,G,Y}, {G,Y,W} and {Y,D,W,N,E} residues respectively, whereas vitamins preferred {Y,F,S,W,T,G,H} residues for the interaction with proteins. Furthermore, compositional information of preferred and non-preferred residues along with patterns-specificity was also observed within different vitamin-classes. Vitamins A, B and B6 preferred {F,I,W,Y,L,V}, {S,Y,G,T,H,W,N,E} and {S,T,G,H,Y,N} interacting residues respectively. It suggested that protein-binding patterns of vitamins are different from other ligands, and motivated us to develop separate predictor for vitamins and their sub-classes. The four different prediction modules, (i) vitamin interacting residues (VIRs), (ii) vitamin-A interacting residues (VAIRs), (iii) vitamin-B interacting residues (VBIRs) and (iv) pyridoxal-5-phosphate (vitamin B6) interacting residues (PLPIRs) have been developed. We applied various classifiers of SVM, BayesNet, NaiveBayes, ComplementNaiveBayes, NaiveBayesMultinomial, RandomForest and IBk etc., as machine learning techniques, using binary and Position-Specific Scoring Matrix (PSSM) features of protein sequences. Finally, we selected best performing SVM modules and obtained highest MCC of 0.53, 0.48, 0.61, 0.81 for VIRs, VAIRs, VBIRs, PLPIRs respectively, using PSSM-based evolutionary information. All the modules developed in this study have been trained and tested on non-redundant datasets and evaluated using five-fold cross-validation technique. The performances were also evaluated on the balanced and different independent datasets.ConclusionsThis study demonstrates that it is possible to predict VIRs, VAIRs, VBIRs and PLPIRs from evolutionary information of protein sequence. In order to provide service to the scientific community, we have developed web-server and standalone software VitaPred (http://crdd.osdd.net/raghava/vitapred/).

Dataset Information

Evolutionary approach to predicting the binding site residues of a protein from its primary sequence.

Publications

Evolutionary approach to predicting the binding site residues of a protein from its primary sequence.

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