Fold recognition and accurate query-template alignment by a combination of PSI-BLAST and threading

A homology-based structure prediction method ideally gives both a correct fold assignment and an accurate query-template alignment. In this article we show that the combination of two existing methods, PSI-BLAST and threading, leads to significant enhancement in the success rate of fold recognition. The combined approach, termed COBLATH, also yields much higher alignment accuracy than found in previous studies. It consists of two-way searches both by PSI-BLAST and by threading. In the PSI-BLAST portion, a query is used to search for hits in a library of potential templates and, conversely, each potential template is used to search for hits in a library of queries. In the threading portion, the scoring function is the sum of a sequence profile and a 6x6 substitution matrix between predicted query and known template secondary structure and solvent exposure. "Two-way" in threading means that the query's sequence profile is used to match the sequences of all potential templates and the sequence profiles of all potential templates are used to match the query's sequence. When tested on a set of 533 nonhomologous proteins, COBLATH was able to assign folds for 390 (73%). Among these 390 queries, 265 (68%) had root-mean-square deviations (RMSDs) of less than 8 A between predicted and actual structures. Such high success rate and accuracy make COBLATH an ideal tool for structural genomics.