Ab initio methods.
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Computational Biology↗
Biomedical subjects
Dylan Chivian
Publications and source records attributed to Dylan Chivian.
Automated prediction of CASP-5 structures using the Robetta server.
Robetta is a fully automated protein structure prediction server that uses the Rosetta fragment-insertion method. It combines template-based and de novo structure prediction methods in an attempt to produce high quality models that cover every residue of a submitted sequence. The first step in the procedure is the automatic detection of the locations of domains and selection of the appropriate modeling protocol for each domain. For domains matched to a homolog with an experimentally characterized structure by PSI-BLAST or Pcons2, Robetta uses a new alignment method, called K*Sync, to align the query sequence onto the parent structure. It then models the variable regions by allowing them to explore conformational space with fragments in fashion similar to the de novo protocol, but in the context of the template. When no structural homolog is available, domains are modeled with the Rosetta de novo protocol, which allows the full length of the domain to explore conformational space via fragment-insertion, producing a large decoy ensemble from which the final models are selected. The Robetta server produced quite reasonable predictions for targets in the recent CASP-5 and CAFASP-3 experiments, some of which were at the level of the best human predictions.
Algorithms↗
Rosetta predictions in CASP5: successes, failures, and prospects for complete automation.
We describe predictions of the structures of CASP5 targets using Rosetta. The Rosetta fragment insertion protocol was used to generate models for entire target domains without detectable sequence similarity to a protein of known structure and to build long loop insertions (and N-and C-terminal extensions) in cases where a structural 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 proteins that were incorrectly parsed into domains and for topologically complex (high contact order) proteins 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 identify the steps that remain to be automated.
Algorithms↗
De novo prediction of three-dimensional structures for major protein families.
We use the Rosetta de novo structure prediction method to produce three-dimensional structure models for all Pfam-A sequence families with average length under 150 residues and no link to any protein of known structure. To estimate the reliability of the predictions, the method was calibrated on 131 proteins of known structure. For approximately 60% of the proteins one of the top five models was correctly predicted for 50 or more residues, and for approximately 35%, the correct SCOP superfamily was identified in a structure-based search of the Protein Data Bank using one of the models. This performance is consistent with results from the fourth critical assessment of structure prediction (CASP4). Correct and incorrect predictions could be partially distinguished using a confidence function based on a combination of simulation convergence, protein length and the similarity of a given structure prediction to known protein structures. While the limited accuracy and reliability of the method precludes definitive conclusions, the Pfam models provide the only tertiary structure information available for the 12% of publicly available sequences represented by these large protein families.
Calibration↗