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

A homology-based structure prediction method ideally gives both a correct f old 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 a ccuracy than found in previous studies. It consists of two-way searches bot h 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, eac h 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 profi le and a 6x6 substitution matrix between predicted query and known template secondary structure and solvent exposure. "Two-way" in threading means tha t the query's sequence profile is used to match the sequences of all potent ial 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 p roteins, COBLATH was able to assign folds for 390 (73%). Among these 390 qu eries, 265 (68%) had root-mean-square deviations (RMSDs) of less than 8 Ang strom between predicted and actual structures. Such high success rate and a ccuracy make COBLATH an ideal tool for structural genomics, Proteins 2001;4 2:23-37. (C) 2000 Wiley-Liss, Inc.