Journal Article

INTREPID—INformation-theoretic TREe traversal for Protein functional site IDentification

Sriram Sankararaman and Kimmen Sjölander

in Bioinformatics

Volume 24, issue 21, pages 2445-2452
Published in print November 2008 | ISSN: 1367-4803
Published online September 2008 | e-ISSN: 1460-2059 | DOI:

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Motivation: Identification of functionally important residues in proteins plays a significant role in biological discovery. Here, we present INTREPID—an information–theoretic approach for functional site identification that exploits the information in large diverse multiple sequence alignments (MSAs). INTREPID uses a traversal of the phylogeny in combination with a positional conservation score, based on Jensen–Shannon divergence, to rank positions in an MSA. While knowledge of protein 3D structure can significantly improve the accuracy of functional site identification, since structural information is not available for a majority of proteins, INTREPID relies solely on sequence information. We evaluated INTREPID on two tasks: predicting catalytic residues and predicting specificity determinants.

Results: In catalytic residue prediction, INTREPID provides significant improvements over Evolutionary Trace, ConSurf as well as over a baseline global conservation method on a set of 100 manually curated enzymes from the Catalytic Site Atlas. In particular, INTREPID is able to better predict catalytic positions that are not globally conserved and hence, attains improved sensitivity at high values of specificity. We also investigated the performance of INTREPID as a function of the evolutionary divergence of the protein family. We found that INTREPID is better able to exploit the diversity in such families and that accuracy improves when homologs with very low sequence identity are included in an alignment. In specificity determinant prediction, when subtype information is known, INTREPID-SPEC, a variant of INTREPID, attains accuracies that are competitive with other approaches for this task.

Availability: INTREPID is available for 16919 families in the PhyloFacts resource (


Supplementary information: Relevant online supplementary material is available at

Journal Article.  7167 words.  Illustrated.

Subjects: Bioinformatics and Computational Biology

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