PROTEINS: Structure, Function, and Genetics 23:356-369 (1995) Threading a Database of Protein Cores

ABSTRACT We present an analysis of 10 blind predictions prepared for a recent confer-ence, “Critical Assessment of Techniques for Protein Structure Prediction.” ’ The sequences of these proteins are not detectably similar to those of any protein in the structure database then available, but we attempted, by a thread-ing method, to recognize similarity to known domain folds. Four of the 10 proteins, as we subsequently learned, do indeed show signifi-cant similarity to then-known structures. For 2 of these proteins the predictions were accurate, in the sense that a similar structure was at or near the top of the list of threading scores, and the threading alignment agreed well with the corresponding structural alignment. For the best predicted model mean alignment error rel-ative to the optimal structural alignment was 2.7 residues, arising entirely from small “regis-ter shifts ” of strands or helices. In the analysis we attempt to identify factors responsible for these successes and failures. Since our thread-ing method does not use gap penalties, we may readily distinguish between errors arising from our prior definition of the “cores ” of known structures and errors arising from inherent lim-itations in the threading potential. It would ap-pear from the results that successful substruc-ture recognition depends most critically on accurate definition of the “fold ” of a database protein. This definition must correctly delin-eate substructures that are, and are not, likely to be conserved during protein evolution