Computational design of closely related proteins that adopt two well-defined but structurally divergent folds
Open Access
- 18 March 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (13), 7208-7215
- https://doi.org/10.1073/pnas.1914808117
Abstract
The plasticity of naturally occurring protein structures, which can change shape considerably in response to changes in environmental conditions, is critical to biological function. While computational methods have been used for de novo design of proteins that fold to a single state with a deep free-energy minimum [P.-S. Huang, S. E. Boyken, D. Baker, Nature 537, 320–327 (2016)], and to reengineer natural proteins to alter their dynamics [J. A. Davey, A. M. Damry, N. K. Goto, R. A. Chica, Nat. Chem. Biol. 13, 1280–1285 (2017)] or fold [P. A. Alexander, Y. He, Y. Chen, J. Orban, P. N. Bryan, Proc. Natl. Acad. Sci. U.S.A. 106, 21149–21154 (2009)], the de novo design of closely related sequences which adopt well-defined but structurally divergent structures remains an outstanding challenge. We designed closely related sequences (over 94% identity) that can adopt two very different homotrimeric helical bundle conformations—one short (∼66 Å height) and the other long (∼100 Å height)—reminiscent of the conformational transition of viral fusion proteins. Crystallographic and NMR spectroscopic characterization shows that both the short- and long-state sequences fold as designed. We sought to design bistable sequences for which both states are accessible, and obtained a single designed protein sequence that populates either the short state or the long state depending on the measurement conditions. The design of sequences which are poised to adopt two very different conformations sets the stage for creating large-scale conformational switches between structurally divergent forms.Funding Information
- HHS | National Institutes of Health (S10OD018455)
- Chan Zuckerberg (Biohub)
This publication has 50 references indexed in Scilit:
- Determination of the Structures of Symmetric Protein Oligomers from NMR Chemical Shifts and Residual Dipolar CouplingsJournal of the American Chemical Society, 2011
- Alternate States of Proteins Revealed by Detailed Energy Landscape MappingJournal of Molecular Biology, 2011
- Rosetta3Methods in Enzymology, 2010
- Facile measurement of 1H–15N residual dipolar couplings in larger perdeuterated proteinsJournal of Biomolecular NMR, 2010
- A minimal sequence code for switching protein structure and functionProceedings of the National Academy of Sciences of the United States of America, 2009
- Simultaneous prediction of protein folding and docking at high resolutionProceedings of the National Academy of Sciences of the United States of America, 2009
- Direct single-molecule observation of a protein living in two opposed native structuresProceedings of the National Academy of Sciences of the United States of America, 2009
- Mutations as trapdoors to two competing native conformations of the Rop-dimerProceedings of the National Academy of Sciences of the United States of America, 2007
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997
- NMRPipe: A multidimensional spectral processing system based on UNIX pipesJournal of Biomolecular NMR, 1995