Latest
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Increased Diels-Alderase activity through backbone remodeling guided by Foldit players
Eiben, C. B., Siegel J. B., Bale J. B. et al. Nature biotechnology. 30(2), 190-2. (2012) Computational enzyme design holds promise for the production of renewable fuels, drugs and chemicals. De novo enzyme design has generated catalysts for several reactions, but with lower catalytic efficiencies than naturally occurring enzymes. Here we report the use of game-driven crowdsourcing to enhance the activity…
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Solution structure of a minor and transiently formed state of a T4 lysozyme mutant
Bouvignies, G., Vallurupalli P., et al. Nature. 477(7362), 111-4. (2011) Proteins are inherently plastic molecules, whose function often critically depends on excursions between different molecular conformations (conformers). However, a rigorous understanding of the relation between a protein’s structure, dynamics and function remains elusive. This is because many of the conformers on its energy landscape are only transiently formed…
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Algorithm discovery by protein folding game players
Khatib, F., Cooper S., Tyka M. D., Xu K., Makedon I., Popovic Z., et al. Proc Natl Acad Sci USA (2011) To determine whether high performing Foldit player strategies could be collectively codified, we augmented the Foldit gameplay mechanics with tools for players to encode their folding strategies as “recipes” and to share their recipes…
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Crystal structure of a monomeric retroviral protease solved by protein folding game players
Khatib, F., DiMaio F., Contenders Group F., Void Crushers Group F. et al. Nature Structural & Molecular Biology (2011) Following the failure of a wide range of attempts to solve the crystal structure of the Mason-Pfizer monkey virus (M-PMV) retroviral protease by molecular replacement, we challenged players of the protein folding game Foldit to produce…
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Computational design of protein inhibitors of Spanish and avian flu hemagglutinin
Fleishman, S. J., Whitehead T. A., et al. Science 332, 816-821. (2011) We developed a new computational method for designing protein interactions and applied it to the design of anti-flu hemagglutinin inhibitors. The proteins were designed using computational resources generously provided by Rosetta @ Home participants and inhibited the function of the hemagglutinin flu coat…
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Improved molecular replacement by density- and energy-guided protein structure optimization
DiMaio, F., Terwilliger T. C et al. Nature (2011) We show that the crystallographic phase problem can be solved using distant evolutionary relationships by combining algorithms for protein structure modelling with those developed for crystallographic structure determination. Ingegrating Rosetta structure modelling with Autobuild chain tracing yielded high-resolution structures for 8 of 13 X-ray diffraction data…
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Determining large protein structures (>200 amino acids) from limited NMR data using Rosetta
Raman, Lange et al, Science, 327, 1014-8. (2010) Large protein structures can now be determined by incorporating backbone-only NMR data into Rosetta. Shown here is the structural comparison of ALG13 (201 amino acids) determined.(A) computationally using RDCs and backbone NH-NH NOEs. (B) experimentally by conventional NMR methods (PDB id : 2jzc) Nuclear Magnetic Resonance (NMR) is…
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Computational design and optimization of Kemp eliminases
Rothlisberger D., Khersonsky O. et al, Nature, 453, 164-6. (2008) Khersonsky O., Rothlisberger D. et al, J Mol Biol, 396(4), 1025-42. (2010) We designed several enzymes that catalyze Kemp elimination, a model reaction for proton transfer from carbon. These enzymes utilize two catalytic motifs and enhance the reaction rate up to 105-fold with multiple turnovers. …