FOLD ASSIGNMENTS FOR AMINO-ACID-SEQUENCES OF THE CASP2 EXPERIMENT

New and newly extended methods for fold assignment were tested for the ir abilities to assign folds to amino acid target sequences of unknown three-dimensional structure. These target sequences, released through the CASP2 experiment, are not obviously related to any sequence of kn own three-dimensional (3D) structure. We assigned 3D folds to target s equences and filed these predictions with CASP2 before their 3D struct ures were released. The methods tested were (1) Environmental 3D profi les of Bowie and colleagues [Bowie, J.U., Luthy, R., Eisenberg, D. Sci ence 253:164-170, 1991]; (2) A variation of this is termed Directional Profiles; (3) The H3P2 five-dimensional sequence-structure substituti on matrix of Rice and Eisenberg [Rice, D., Eisenberg, D.J. Mol. Biol. 267:1026-1037, 1997]; and (4) The Sequence Derived Property methods of Fischer and Eisenberg [Fischer, D., Eisenberg, D. Prot. Sci. 5:947-95 5, 1996]. When the 3D structures of the sequences were released, 17 of our predictions were evaluated. Of these 17, we assigned high probabi lities to 11, of which 9 were correct. Five of these correct predictio ns were of known 3D structures similar to the targets and four of thes e were of new folds. The evaluation demonstrated that our methods were effective in assigning the proper fold to more than half of the CASP2 targets with known folds (5/9) and also were able to detect half of t he sequences that corresponded to no known folds (4/8). Even when the correct fold is assigned to a sequence, proper alignment of the sequen ce to the structure remains a challenge. Our methods were able to prod uce accurate alignments (<1.2 mean residue shift error from the struct ural alignment) for four of the targets, including the particularly di fficult alignment (only 7% residue identity in the structurally aligne d regions) of the ferrochelatase sequence to the fold of a periplasmic binding protein. (C) 1998 Wiley-Liss, Inc.