PROTEIN FOLD RECOGNITION BY MAPPING PREDICTED SECONDARY STRUCTURES

A strategy is presented for protein fold recognition from secondary st ructure assignments (alpha-helix and beta-strand). The method can dete ct similarities between protein folds in the absence of sequence simil arity. Secondary structure mapping first identifies all possible match es (maps) between a query string of secondary structures and the secon dary structures of protein domains of known three-dimensional structur e. The maps are then passed through a series of structural filters to remove those that do not obey simple rules of protein structure. The s urviving maps are ranked by scores from the alignment of predicted and experimental accessibilities. Searches made with secondary structure assignments for a test set of 11 fold-families put the correct sequenc e-dissimilar fold in the first rank 8/11 times. With cross-validated p redictions of secondary structure this drops to 4/11 which compares fa vourably with the widely used THREADER program (1/11). The structural class is correctly predicted 10/11 times by the method in contrast to 5/11 for THREADER. The new technique obtains comparable accuracy in th e alignment of amino acid residues and secondary structure elements. S earches are also performed with published secondary structure predicti ons for the von-Willebrand factor type A domain, the proteasome 20 S a lpha subunit and the phosphotyrosine interaction domain. These searche s demonstrate how the method can find the correct fold for a protein f rom a carefully constructed secondary structure prediction, multiple s equence alignment and distance restraints. Scans with experimentally d etermined secondary structures and accessibility, recognise the correc t fold with high alignment accuracy (86% on secondary structures). Thi s suggests that the accuracy of mapping will improve alongside any imp rovements in the prediction of secondary structure or accessibility. A pplication to NMR structure determination is also discussed. (C) 1996 Academic Press Limited