Bioinformatics Advance Access originally published online on May 29, 2008
Bioinformatics 2008 24(14):1575-1582; doi:10.1093/bioinformatics/btn248
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Using inferred residue contacts to distinguish between correct and incorrect protein models
1UCLA-DOE Institute for Genomics & Proteomics, Molecular Biology Institute and 2Howard Hughes Medical Institute, Departments of Chemistry & Biochemistry & Biological Chemistry, Box 951570, UCLA, Los Angeles, CA 90095, USA
*To whom correspondence should be addressed.
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Abstract |
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Motivation: The de novo prediction of 3D protein structure is enjoying a period of dramatic improvements. Often, a remaining difficulty is to select the model closest to the true structure from a group of low-energy candidates. To what extent can inter-residue contact predictions from multiple sequence alignments, information which is orthogonal to that used in most structure prediction algorithms, be used to identify those models most similar to the native protein structure?
Results: We present a Bayesian inference procedure to identify residue pairs that are spatially proximal in a protein structure. The method takes as input a multiple sequence alignment, and outputs an accurate posterior probability of proximity for each residue pair. We exploit a recent metagenomic sequencing project to create large, diverse and informative multiple sequence alignments for a test set of 1656 known protein structures. The method infers spatially proximal residue pairs in this test set with good accuracy: top-ranked predictions achieve an average accuracy of 38% (for an average 21-fold improvement over random predictions) in cross-validation tests. Notably, the accuracy of predicted 3D models generated by a range of structure prediction algorithms strongly correlates with how well the models satisfy probable residue contacts inferred via our method. This correlation allows for confident rejection of incorrect structural models.
Availability: An implementation of the method is freely available at http://www.doe-mbi.ucla.edu/services
Contact: david{at}mbi.ucla.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
Associate Editor: Burkhard Rost
Received on March 15, 2008; revised on May 7, 2008; accepted on May 25, 2008
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