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Published online before print March 9, 2004, 10.1110/ps.03465504
Protein Science (2004), 13:884-892. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Prediction of functional sites by analysis of sequence and structure conservation

Anna R. Panchenko1, Fyodor Kondrashov2 and Stephen Bryant1

1 Computational Biology Branch, National Center for Biotechnology Information (NCBI), National Institutes of Health (NIH), Bethesda, Maryland 20894, USA
2 Section of Evolution and Ecology, University of California, Davis, California 95616, USA

(RECEIVED October 1, 2003; FINAL REVISION December 2, 2003; ACCEPTED December 3, 2003)



Abstract

We present a method for prediction of functional sites in a set of aligned protein sequences. The method selects sites which are both well conserved and clustered together in space, as inferred from the 3D structures of proteins included in the alignment. We tested the method using 86 alignments from the NCBI CDD database, where the sites of experimentally determined ligand and/or macromolecular interactions are annotated. In agreement with earlier investigations, we found that functional site predictions are most successful when overall background sequence conservation is low, such that sites under evolutionary constraint become apparent. In addition, we found that averaging of conservation values across spatially clustered sites improves predictions under certain conditions: that is, when overall conservation is relatively high and when the site in question involves a large macromolecular binding interface. Under these conditions it is better to look for clusters of conserved sites than to look for particular conserved sites.

Keywords: protein domains; prediction of functional residues; evolutionary conservation

Reprint requests to: Anna R. Panchenko, Computational Biology Branch, NCBI, Bldg. 38A, Rm. 8N805, NIH, Bethesda, MD 20894, USA; e-mail: panch{at}ncbi.nlm.nih.gov; fax (301) 435-7794.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03465504.


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