Assessment of protein fold predictions from sequence information: the predicted alpha/beta doubly wound fold of the von Willebrand factor type A domain is similar to its crystal structure.

The fold of the von Willebrand Factor type A domain (vWF-A) was predicted to be similar to an alpha/beta doubly wound fold in the GTP-binding domain of ras-p21, despite the lack of sequence or functional similarity. This was subsequently confirmed by the vWF-A crystal structure from complement receptor type 3. The prediction is now reviewed. The vWF-A secondary structure was predicted with 62 to 75% accuracy and 12 of the 13 secondary structure elements were identified correctly. Accessibility predictions were 69 to 71% accurate. The fold recognition analysis was confirmed, but was much improved by averaging the results from 70 complete vWF-A sequences. The related folds of ras-P21 and flavodoxin scored highly. In addition, both the mapping of the predicted vWF-A secondary structure elements with those in 12 known alpha/beta folds and two Asp residues at the C-terminal ends of two adjacent beta-strands matched well with ras-p21 and flavodoxin. The predicted Mg(2+)-binding site, two disulphide bridges and the secondary structure topology were largely accurate. The exception is the reversal of a beta-hairpin at one end of the central beta-sheet. We conclude that non-homologous folds with dissimilar functions can be predicted from sequence data with reasonable accuracy, and that the accuracy in this case was principally limited at the periphery of the fold.