Predicting functionally important residues from sequence conservation. Author John Capra, Mona Singh Publication Year 2007 Type Journal Article 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/ Keywords Structure-Activity Relationship, Molecular Sequence Data, Evolution, Molecular, Proteins, Algorithms, Conserved Sequence, Sequence Alignment, Amino Acid Sequence, Sequence Homology, Nucleic Acid, Sequence Analysis, Protein, Amino Acids Journal Bioinformatics Volume 23 Issue 15 Pages 1875-82 Date Published 08/2007 Alternate Journal Bioinformatics Google ScholarBibTeXEndNote X3 XML