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Bioinformatics Vol. 18 no. 12 2002
Pages 1658-1665
© 2002 Oxford University Press

Structure–dependent sequence alignment for remotely related proteins

An-Suei Yang

Department of Pharmacology and Columbia Genome Center, Columbia University, 630 West 168th street, PH 7 W Room 318, New York, NY 10032, USA

Received on January 2, 2002 ; revised on April 10, 2002 ; accepted on May 24, 2002

Motivation: The quality of a model structure derived from a comparative modeling procedure is dictated by the accuracy of the predicted sequence–template alignment. As the sequence–template pairs are increasingly remote in sequence relationship, the prediction of the sequence–template alignments becomes increasingly problematic with sequence alignment methods. Structural information of the template, used in connection with the sequence relationship of the sequence–template pair, could significantly improve the accuracy of the sequence–template alignment. In this paper, we describe a sequence–template alignment method that integrates sequence and structural information to enhance the accuracy of sequence–template alignments for distantly related protein pairs.

Results: The structure-dependent sequence alignment (SDSA) procedure was optimized for coverage and accuracy on a training set of 412 protein pairs; the structures for each of the training pairs are similar (RMSD<~4Å) but the sequence relationship is undetectable (average pair-wise sequence identity = 8%). The optimized SDSA procedure was then applied to extend PSI-BLAST local alignments by calculating the global alignments under the constraint of the residue pairs in the local alignments. This composite alignment procedure was assessed with a testing set of 1421 protein pairs, of which the pair-wise structures are similar (RMSD<~4Å) but the sequences are marginally related at best in each pair (average pair-wise sequence identity = 13%). The assessment showed that the composite alignment procedure predicted more aligned residues pairs with an average of 27% increase in correctly aligned residues over the standard PSI-BLAST alignments for the protein pairs in the testing set.

Availability: All the computational and assessment procedures have been implemented in the integrated computational system PrISM.1 (Protein Informatics System for Modeling). The system and associated databases for LINUX systems can be downloaded from the website: http://www.columbia.edu/~ay1/

Contact: ay1{at}columbia.edu


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