Enhanced functional annotation of protein sequences via the use of structural descriptors

In order to circumvent limitations of sequence based methods in the process of making functional predictions for proteins, we have developed a methodo logy that uses a sequence-to-structure-to-function paradigm. First, an appr oximate three-dimensional structure is predicted. Then, a three-dimensional descriptor of the functional site, termed a Fuzzy Functional Form, or FFF, is used to screen the structure for the presence of the functional site of interest (Fetrow et al., 1998; Fetrow and Skolnick, 1998). Previously, a d isulfide oxidoreductase FFF was developed and applied to predicted structur es obtained from a small structural database. Here, using a substantially l arger structural database, we expand the analysis of the disulfide oxidored uctase FFF to the B. subtilis genome. To ascertain the performance of the F FF, its results are compared to those obtained using both the sequence alig nment method BLAST and three local sequence motif databases: PRINTS, Prosit e, and Blocks. The FFF method is then compared in detail to Blocks and it i s shown that the FFF is more flexible and sensitive in finding a specific f unction in a set of unknown proteins. In addition, the estimated false posi tive rate of function prediction is significantly lower using the FFF struc tural motif, rather than the standard sequence motif methods. We also prese nt a second FFF and describe a specific example of the results of its whole -genome application to D. melanogaster using a newer threading algorithm. O ur results from all of these studies indicate that the addition of three-di mensional structural in-formation adds significant value in the prediction of biochemical function of genomic sequences. (C) 2001 Academic Press.