Defrosting the frozen approximation: PROSPECTOR - A new approach to threading

PROSPECTOR (PROtein Structure Predictor Employing Combined Threading to Opt imize Results) is a new threading approach that uses sequence profiles to g enerate an initial probe-template alignment and then uses this "partly thaw ed" 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 sequenc es with a FASTA E-score less than 10, Thus, a total of four scoring functio ns 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 correct ly identified in the top position. Next, the set of the top 20 scoring sequ ences (four scoring functions times the top five structures) is used to con struct a protein-specific pair potential based on consensus sidechain conta cts occurring in 25% of the structures. In subsequent threading iterations, this protein-specific pair potential, when combined in a composite manner, is found to be more sensitive in identifying the correct pairs than when t he original statistical potential is used, and it increases the number of r ecognized structures for the combined scoring functions, termed PROSPECTOR2 , to a total of 61 Fischer pairs identified in the top position. Applicatio n to a second, smaller Fischer database of 27 probe-template pairs places 1 8 (17) structures in the top position for PROSPECTOR1 (PROSPECTOR2), Overal l, 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 identif y correct probe-template pairs is significantly enhanced, Finally, a web se rver has been established for use by the academic community (http://bioinfo rmatics.danforthcenter.org/services/threading.html). Proteins 2001;42:319-3 31, (C) 2000 Wiley-Liss, Inc.