Assessment of protein fold predictions from sequence information: The predicted alpha/beta doubly wound fold of the vonWillebrand 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 Mg2+-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. (C) 1996 Academic Press Limited