title: Prediction of Stable Globular Proteins Using Negative Design with Non-native Backbone Ensembles.
abstract: Accurate predictions of protein stability have great potential to accelerate progress in computational protein design, yet the correlation of predicted and experimentally determined stabilities remains a significant challenge. To address this problem, we have developed a computational framework based on negative multistate design in which sequence energy is evaluated in the context of both native and non-native backbone ensembles. This framework was validated experimentally with the design of ten variants of streptococcal protein G domain β1 that retained the wild-type fold, and showed a very strong correlation between predicted and experimental stabilities (R(2) = 0.86). When applied to four different proteins spanning a range of fold types, similarly strong correlations were also obtained. Overall, the enhanced prediction accuracies afforded by this method pave the way for new strategies to facilitate the generation of proteins with novel functions by computational protein design.
authors.affiliation: Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Davey
authors.affiliation: Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Damry
authors.affiliation: Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Euler
authors.affiliation: Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Goto
authors.affiliation: Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada. Electronic address: rchica@uottawa.ca.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Chica
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010940:Plant Proteins / Q000737:chemistry; D017510:Protein Folding; D055550:Protein Stability; D015842:Serine Proteinase Inhibitors / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; C034284:IgG Fc-binding protein, Streptococcus; D010940:Plant Proteins; D015842:Serine Proteinase Inhibitors