Abstract
The prediction of the structures of proteins without detectable sequence similarity to any protein of known structure remains an outstanding scientific challenge. Here we report significant progress in this area. We first describe de novo blind structure predictions of unprecendented accuracy we made for two proteins in large families in the recent CASP11 blind test of protein structure prediction methods by incorporating residue-residue co-evolution information in the Rosetta structure prediction program. We then describe the use of this method to generate structure models for 58 of the 121 large protein families in prokaryotes for which three-dimensional structures are not available. These models, which are posted online for public access, provide structural information for the over 400,000 proteins belonging to the 58 families and suggest hypotheses about mechanism for the subset for which the function is known, and hypotheses about function for the remainder.
Highlights
Despite substantial efforts over decades, high-resolution structure prediction is currently limited to proteins that have homologs of known structure, or small proteins where thorough sampling of the conformational space is possible (
In the recent CASP11 (11th critical assessment of techniques for protein structure prediction) blind test of protein structure prediction methods, we predicted the structures of proteins from large families with no representatives of known structure by integrating co-evolution derived contact information from GREMLIN (Kamisetty et al, 2013) into the Rosetta structure prediction methodology (Simons et al, 1999; Rohl et al, 2004; Raman et al, 2009)
We identified 100 families satisfying these criteria in Escherichia coli (Gram-negative, Proteobacteria), and an additional 22, 5, and 4 families in Bacillus subtilis (Gram-positive, Firmicutes bacterium), Halobacterium salinarum (Euryarchaeota), and Sulfolobus solfataricus (Crenarchaeota), respectively (Supplementary file 1)
Summary
Despite substantial efforts over decades, high-resolution structure prediction is currently limited to proteins that have homologs of known structure, or small proteins where thorough sampling of the conformational space is possible (
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