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Bioinformatics Advance Access first published online on May 22, 2007
This version published online on June 1, 2007
Bioinformatics, doi:10.1093/bioinformatics/btm270
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Predicting functionally important residues from sequence conservation

John A. Capra and Mona Singh *

Department of Computer Science, Princeton University, Princeton, NJ 08540, USA

*To whom correspondence should be addressed. Prof. Mona Singh, E-mail: msingh{at}cs.princeton.edu


  Abstract

Motivation: All residues in a protein are not equally important. Some are essential for the proper structure and function of the protein, whereas others can be readily replaced. Conservation analysis is one of the most widely used methods for predicting these functionally important residues in protein sequences.

Results: We introduce an information-theoretic approach for estimating sequence conservation based on Jensen-Shannon divergence. We also develop a general heuristic that considers the estimated conservation of sequentially neighboring sites. In large-scale testing, we demonstrate that our combined approach outperforms previous conservation-based measures in identifying functionally important residues; in particular, it is significantly better than the commonly used Shannon entropy measure. We find that considering conservation at sequential neighbors improves the performance of all methods tested. Our analysis also reveals that many existing methods that attempt to incorporate the relationships between amino acids do not lead to better identification of functionally important sites. Finally, we find that while conservation is highly predictive in identifying catalytic sites and residues near bound ligands, it is much less effective in identifying residues in protein-protein interfaces.

Availability: Data sets and code for all conservation measures evaluated are available at http://compbio.cs.princeton.edu/conservation/.

Associate Editor: Prof. Keith Crandall

Received on March 26, 2007; revised on May 4, 2007; accepted on May 10, 2007

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