Defrosting the frozen approximation: PROSPECTOR— A new approach to threading
✍ Scribed by Jeffrey Skolnick; Daisuke Kihara
- Publisher
- John Wiley and Sons
- Year
- 2001
- Tongue
- English
- Weight
- 155 KB
- Volume
- 42
- Category
- Article
- ISSN
- 0887-3585
No coin nor oath required. For personal study only.
✦ Synopsis
PROSPECTOR (PROtein Structure Predictor Employing Combined Threading to Optimize Results) is a new threading approach that uses sequence profiles to generate an initial probetemplate alignment and then uses this "partly thawed" alignment in the evaluation of pair interactions. Two types of sequence profiles are used: the close set, composed of sequences in which sequence identity lies between 35% and 90%; and the distant set, composed of sequences with a FASTA E-score less than 10. Thus, a total of four scoring functions are used in a hierarchical method: the close (distant) sequence profiles screen a structural database to provide an initial alignment of the probe sequence in each of the templates. The same database is then screened with a scoring function composed of sequence plus secondary structure plus pair interaction profiles. This combined hierarchical threading method is called PROSPECTOR1. For the original Fischer database, 59 of 68 pairs are correctly identified in the top position. Next, the set of the top 20 scoring sequences (four scoring functions times the top five structures) is used to construct a proteinspecific pair potential based on consensus sidechain contacts occurring in 25% of the structures. In subsequent threading iterations, this proteinspecific pair potential, when combined in a composite manner, is found to be more sensitive in identifying the correct pairs than when the original statistical potential is used, and it increases the number of recognized structures for the combined scoring functions, termed PROSPECTOR2, to a total of 61 Fischer pairs identified in the top position. Application to a second, smaller Fischer database of 27 probe-template pairs places 18 (17) structures in the top position for PROSPECTOR1 (PROSPECTOR2). Overall, these studies show that the use of pair interactions as assessed by the improved Z-score enhances the specificity of probe-template matches. Thus, when the hierarchy of scoring functions is combined, the ability to identify correct probetemplate pairs is significantly enhanced. Finally, a web server has been established for use by the academic community (http://bioinformatics.danforthcenter.org/services/threading.html). Proteins 2001;42:319 -331.