PROTEIN-STRUCTURE PREDICTION BY THREADING METHODS - EVALUATION OF CURRENT TECHNIQUES

This paper evaluates the results of a protein structure prediction con test. The predictions were made using threading procedures, which empl oy techniques for aligning sequences with 3D structures to select the correct fold of a given sequence from a set of alternatives. Nine diff erent teams submitted 86 predictions, on a total of 21 target proteins with little or no sequence homology to proteins of known structure, T he 3D structures of these proteins were newly determined by experiment al methods, but not yet published or otherwise available to the predic tors. The predictions, made from the amino acid sequence alone, thus r epresent a genuine test of the current performance of threading method s. Only a subset of all. the predictions is evaluated here. It corresp onds to the 44 predictions submitted for the 11 target proteins seen t o adopt known folds. The predictions for the remaining 10 proteins wer e not analyzed, although weak similarities with known folds may also e xist in these proteins. We find that threading methods are capable of identifying the correct fold in many cases, but not reliably enough as yet. Every team predicts correctly a different set of targets, with v irtually all targets predicted correctly by at least one team. Also, c ommon folds such as TIM barrels are recognized more readily than folds with only a few known examples. However, quite surprisingly, the qual ity of the sequence-structure alignments, corresponding to correctly r ecognized folds, is generally very poor, as judged by comparison with the corresponding 3D structure alignments. Thus, threading can present ly not be relied upon to derive a detailed 3D model from the amino aci d sequence. This raises a very intriguing question: how is fold recogn ition achieved? Our analysis suggests that it may be achieved because threading procedures maximize hydrophobic interactions in the protein core, and are reasonably good at recognizing local secondary structure . (C) 1995 Wiley-Liss, Inc.