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Computational design of closely related proteins that adopt two well-defined but structurally divergent folds

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...

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Autores principales: Wei, Kathy Y., Moschidi, Danai, Bick, Matthew J., Nerli, Santrupti, McShan, Andrew C., Carter, Lauren P., Huang, Po-Ssu, Fletcher, Daniel A., Sgourakis, Nikolaos G., Boyken, Scott E., Baker, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132107/
https://www.ncbi.nlm.nih.gov/pubmed/32188784
http://dx.doi.org/10.1073/pnas.1914808117
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author Wei, Kathy Y.
Moschidi, Danai
Bick, Matthew J.
Nerli, Santrupti
McShan, Andrew C.
Carter, Lauren P.
Huang, Po-Ssu
Fletcher, Daniel A.
Sgourakis, Nikolaos G.
Boyken, Scott E.
Baker, David
author_facet Wei, Kathy Y.
Moschidi, Danai
Bick, Matthew J.
Nerli, Santrupti
McShan, Andrew C.
Carter, Lauren P.
Huang, Po-Ssu
Fletcher, Daniel A.
Sgourakis, Nikolaos G.
Boyken, Scott E.
Baker, David
author_sort Wei, Kathy Y.
collection PubMed
description 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.
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spelling pubmed-71321072020-04-09 Computational design of closely related proteins that adopt two well-defined but structurally divergent folds Wei, Kathy Y. Moschidi, Danai Bick, Matthew J. Nerli, Santrupti McShan, Andrew C. Carter, Lauren P. Huang, Po-Ssu Fletcher, Daniel A. Sgourakis, Nikolaos G. Boyken, Scott E. Baker, David Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2020-03-31 2020-03-18 /pmc/articles/PMC7132107/ /pubmed/32188784 http://dx.doi.org/10.1073/pnas.1914808117 Text en Copyright © 2020 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Wei, Kathy Y.
Moschidi, Danai
Bick, Matthew J.
Nerli, Santrupti
McShan, Andrew C.
Carter, Lauren P.
Huang, Po-Ssu
Fletcher, Daniel A.
Sgourakis, Nikolaos G.
Boyken, Scott E.
Baker, David
Computational design of closely related proteins that adopt two well-defined but structurally divergent folds
title Computational design of closely related proteins that adopt two well-defined but structurally divergent folds
title_full Computational design of closely related proteins that adopt two well-defined but structurally divergent folds
title_fullStr Computational design of closely related proteins that adopt two well-defined but structurally divergent folds
title_full_unstemmed Computational design of closely related proteins that adopt two well-defined but structurally divergent folds
title_short Computational design of closely related proteins that adopt two well-defined but structurally divergent folds
title_sort computational design of closely related proteins that adopt two well-defined but structurally divergent folds
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132107/
https://www.ncbi.nlm.nih.gov/pubmed/32188784
http://dx.doi.org/10.1073/pnas.1914808117
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