A novel method for the prediction of protein function based on the sequence-to-structure-to-function paradigm has been developed. First, the tertiary structure of the sequence of interest is predicted from either ab initio folding or threading. Then, using a library of three dimensional descriptors of protein active sites, termed fuzzy functional forms or FFFs, the resulting structures are screened. If the geometry and residue types in the predicted structure match, then the protein is predicted to have the specified molecular function. By way of illustration, predictions of the disulfide oxidoreductase activity of the glutaredoxins and thioredoxins are described. The FFFs correctly identify the active sites in a library of experimental structures as well as in models produced by ab initio folding or threading. This shows that low-to-moderate resolution models whose carbon root mean square deviations from native range from 3.5-6 M-E are sufficient to identify protein active sites.

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