Rosetta predictions in CASP5: Successes, failures, and prospects for complete automation

We describe predictions of the structures of CASP5 targets using Rosetta. The Ro- setta fragment insertion protocol was used to gener- ate models for entire target domains without detect- able sequence similarity to a protein of known structure and to build long loop insertions (and N-and C-terminal extensions) in cases where a struc- tural template was available. Encouraging results were obtained both for the de novo predictions and for the long loop insertions; we describe here the successes as well as the failures in the context of current efforts to improve the Rosetta method. In particular, de novo predictions failed for large pro- teins that were incorrectly parsed into domains and for topologically complex (high contact order) pro- teins with swapping of segments between domains. However, for the remaining targets, at least one of the five submitted models had a long fragment with significant similarity to the native structure. A fully automated version of the CASP5 protocol produced results that were comparable to the human-assisted predictions for most of the targets, suggesting that automated genomic-scale, de novo protein structure prediction may soon be worthwhile. For the three targets where the human-assisted predictions were significantly closer to the native structure, we iden- tify the steps that remain to be automated. Proteins 2003;53:457- 468. © 2003 Wiley-Liss, Inc.