Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

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

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 eithermore » 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.« less

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [3]; ORCiD logo [2]; ORCiD logo [2];  [2]; ORCiD logo [4]; ORCiD logo [5]; ORCiD logo [2]; ORCiD logo [3]; ORCiD logo [3]
+ Show Author Affiliations
  1. Univ. of Washington, Seattle, WA (United States); Univ. of California, Berkeley, CA (United States)
  2. Univ. of California, Santa Cruz, CA (United States)
  3. Univ. of Washington, Seattle, WA (United States)
  4. Stanford Univ., CA (United States)
  5. Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institute of Health
OSTI Identifier:
1625056
Alternate Identifier(s):
OSTI ID: 1646850
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 117; Journal Issue: 13; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Science & Technology - Other Topics

Citation Formats

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., and Baker, David. Computational design of closely related proteins that adopt two well-defined but structurally divergent folds. United States: N. p., 2020. Web. doi:10.1073/pnas.1914808117.
Copy to clipboard
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. United States. https://doi.org/10.1073/pnas.1914808117
Copy to clipboard
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., and Baker, David. Wed . "Computational design of closely related proteins that adopt two well-defined but structurally divergent folds". United States. https://doi.org/10.1073/pnas.1914808117. https://www.osti.gov/servlets/purl/1625056.
Copy to clipboard
@article{osti_1625056,
title = {Computational design of closely related proteins that adopt two well-defined but structurally divergent folds},
author = {Wei, Kathy Y. and Moschidi, Danai and Bick, Matthew J. and Nerli, Santrupti and McShan, Andrew C. and Carter, Lauren P. and Huang, Po-Ssu and Fletcher, Daniel A. and Sgourakis, Nikolaos G. and Boyken, Scott E. and Baker, David},
abstractNote = {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.},
doi = {10.1073/pnas.1914808117},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 13,
volume = 117,
place = {United States},
year = {2020},
month = {3}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1073/pnas.1914808117
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 26 works
Citation information provided by
Web of Science

Figures / Tables:

Fig. 1 Fig. 1: Design and in silico characterization of proteins with two distinct, well-defined ground states. (A) Design concept for protein backbones with a “short” and a “long” state. The backbone consists of a stable base, mobile flipping helices (red), tunable interface, and a flexible hinge (yellow). (B) Tunable interface betweenmore » the inner helices and flipping helices. Each of three positions can be a hydrogen bond (green, “A”) or hydrophobic (black, “X”) layer. (C) Fraction of top 10 scored Rosetta folding predictions that resemble the short, long, or other structure for each permutation of possible interface configurations. (D) Initial design scheme. Starting with the previously characterized protein 2L3HC3_13 (PDB ID 5J0H) (cyan), a monomer is extracted, cut to produce a flipping helix, and reconnected with a hinge to produce the backbone of the short or long state. (E) Final design scheme. Previously characterized proteins 2L3HC3_13 (cyan) and 2L3HC3_23 (blue) are fused via their inner helices, outer helices are trimmed, and the hinge length is chosen such that the flipping helices pack against each other in the long state.« less
All figures and tables (4 total)
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

Combined Covalent-Electrostatic Model of Hydrogen Bonding Improves Structure Prediction with Rosetta
journal, January 2015

  • O’Meara, Matthew J.; Leaver-Fay, Andrew; Tyka, Michael D.
  • Journal of Chemical Theory and Computation, Vol. 11, Issue 2
  • DOI: 10.1021/ct500864r

A Generic Program for Multistate Protein Design
journal, July 2011

Control over overall shape and size in de novo designed proteins
journal, September 2015

  • Lin, Yu-Ru; Koga, Nobuyasu; Tatsumi-Koga, Rie
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 40
  • DOI: 10.1073/pnas.1509508112

Simultaneous Optimization of Biomolecular Energy Functions on Features from Small Molecules and Macromolecules
journal, November 2016

  • Park, Hahnbeom; Bradley, Philip; Greisen, Per
  • Journal of Chemical Theory and Computation, Vol. 12, Issue 12
  • DOI: 10.1021/acs.jctc.6b00819

Rational design of proteins that exchange on functional timescales
journal, October 2017

  • Davey, James A.; Damry, Adam M.; Goto, Natalie K.
  • Nature Chemical Biology, Vol. 13, Issue 12
  • DOI: 10.1038/nchembio.2503

Simultaneous prediction of protein folding and docking at high resolution
journal, October 2009

  • Das, Rhiju; André, Ingemar; Shen, Yang
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 45
  • DOI: 10.1073/pnas.0904407106

NMRFAM-SPARKY: enhanced software for biomolecular NMR spectroscopy
journal, December 2014

Chemical shift-based methods in NMR structure determination
journal, June 2018

  • Nerli, Santrupti; McShan, Andrew C.; Sgourakis, Nikolaos G.
  • Progress in Nuclear Magnetic Resonance Spectroscopy, Vol. 106-107
  • DOI: 10.1016/j.pnmrs.2018.03.002

Direct single-molecule observation of a protein living in two opposed native structures
journal, June 2009

  • Gambin, Y.; Schug, A.; Lemke, E. A.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 25
  • DOI: 10.1073/pnas.0904461106

Principles for designing proteins with cavities formed by curved β sheets
journal, January 2017

  • Marcos, Enrique; Basanta, Benjamin; Chidyausiku, Tamuka M.
  • Science, Vol. 355, Issue 6321
  • DOI: 10.1126/science.aah7389

MetalPDB in 2018: a database of metal sites in biological macromolecular structures
journal, October 2017

  • Putignano, Valeria; Rosato, Antonio; Banci, Lucia
  • Nucleic Acids Research, Vol. 46, Issue D1
  • DOI: 10.1093/nar/gkx989

Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

Modeling Symmetric Macromolecular Structures in Rosetta3
journal, June 2011

The coming of age of de novo protein design
journal, September 2016

  • Huang, Po-Ssu; Boyken, Scott E.; Baker, David
  • Nature, Vol. 537, Issue 7620
  • DOI: 10.1038/nature19946

Accurate computational design of multipass transmembrane proteins
journal, March 2018

Receptor Binding and Membrane Fusion in Virus Entry: The Influenza Hemagglutinin
journal, June 2000

De novo design of protein homo-oligomers with modular hydrogen-bond network-mediated specificity
journal, May 2016

Native protein sequences are close to optimal for their structures
journal, September 2000

  • Kuhlman, B.; Baker, D.
  • Proceedings of the National Academy of Sciences, Vol. 97, Issue 19
  • DOI: 10.1073/pnas.97.19.10383

Self-Assembling 2D Arrays with de Novo Protein Building Blocks
journal, May 2019

  • Chen, Zibo; Johnson, Matthew C.; Chen, Jiajun
  • Journal of the American Chemical Society, Vol. 141, Issue 22
  • DOI: 10.1021/jacs.9b01978

Determination of the Structures of Symmetric Protein Oligomers from NMR Chemical Shifts and Residual Dipolar Couplings
journal, April 2011

  • Sgourakis, Nikolaos G.; Lange, Oliver F.; DiMaio, Frank
  • Journal of the American Chemical Society, Vol. 133, Issue 16
  • DOI: 10.1021/ja111318m

De novo design of bioactive protein switches
journal, July 2019

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

What makes a protein a protein? Hydrophobic core designs that specify stability and structural properties
journal, August 1996

  • Munson, Mary; Balasubramanian, Suganthi; Fleming, Karen G.
  • Protein Science, Vol. 5, Issue 8
  • DOI: 10.1002/pro.5560050813

A minimal sequence code for switching protein structure and function
journal, November 2009

  • Alexander, Patrick A.; He, Yanan; Chen, Yihong
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 50
  • DOI: 10.1073/pnas.0906408106

De novo design of tunable, pH-driven conformational changes
journal, May 2019

Accurate SAXS Profile Computation and its Assessment by Contrast Variation Experiments
journal, August 2013

  • Schneidman-Duhovny, Dina; Hammel, Michal; Tainer, John A.
  • Biophysical Journal, Vol. 105, Issue 4
  • DOI: 10.1016/j.bpj.2013.07.020

Alternate States of Proteins Revealed by Detailed Energy Landscape Mapping
journal, January 2011

  • Tyka, Michael D.; Keedy, Daniel A.; André, Ingemar
  • Journal of Molecular Biology, Vol. 405, Issue 2
  • DOI: 10.1016/j.jmb.2010.11.008

ZiCo:  A Peptide Designed to Switch Folded State upon Binding Zinc
journal, November 2005

  • Cerasoli, Eleonora; Sharpe, Belinda K.; Woolfson, Derek N.
  • Journal of the American Chemical Society, Vol. 127, Issue 43
  • DOI: 10.1021/ja0543604

NMRPipe: A multidimensional spectral processing system based on UNIX pipes
journal, November 1995

  • Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW.
  • Journal of Biomolecular NMR, Vol. 6, Issue 3
  • DOI: 10.1007/BF00197809

FoXS, FoXSDock and MultiFoXS: Single-state and multi-state structural modeling of proteins and their complexes based on SAXS profiles
journal, May 2016

  • Schneidman-Duhovny, Dina; Hammel, Michal; Tainer, John A.
  • Nucleic Acids Research, Vol. 44, Issue W1
  • DOI: 10.1093/nar/gkw389

Mutations as trapdoors to two competing native conformations of the Rop-dimer
journal, October 2007

  • Schug, A.; Whitford, P. C.; Levy, Y.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 45
  • DOI: 10.1073/pnas.0706077104

Ile, Leu, and Val Methyl Assignments of the 723-Residue Malate Synthase G Using a New Labeling Strategy and Novel NMR Methods
journal, November 2003

  • Tugarinov, Vitali; Kay, Lewis E.
  • Journal of the American Chemical Society, Vol. 125, Issue 45
  • DOI: 10.1021/ja030345s

Facile measurement of 1H–15N residual dipolar couplings in larger perdeuterated proteins
journal, August 2010

Influenza-virus membrane fusion by cooperative fold-back of stochastically induced hemagglutinin intermediates
journal, February 2013

RosettaScripts: A Scripting Language Interface to the Rosetta Macromolecular Modeling Suite
journal, June 2011

A De Novo Designed Coiled-Coil Peptide with a Reversible pH-Induced Oligomerization Switch
journal, June 2016

XDS
journal, January 2010

  • Kabsch, Wolfgang
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
  • DOI: 10.1107/S0907444909047337

Joint X-ray and neutron refinement with phenix.refine
journal, October 2010

  • Afonine, Pavel V.; Mustyakimov, Marat; Grosse-Kunstleve, Ralf W.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 11
  • DOI: 10.1107/S0907444910026582

Virus and Cell Fusion Mechanisms
journal, October 2014

RosettaRemodel: A Generalized Framework for Flexible Backbone Protein Design
journal, August 2011

Computational Design of a Single Amino Acid Sequence that Can Switch between Two Distinct Protein Folds
journal, February 2006

  • Ambroggio, Xavier I.; Kuhlman, Brian
  • Journal of the American Chemical Society, Vol. 128, Issue 4
  • DOI: 10.1021/ja054718w

Design of self-assembling transmembrane helical bundles to elucidate principles required for membrane protein folding and ion transport
journal, June 2017

  • Joh, Nathan H.; Grigoryan, Gevorg; Wu, Yibing
  • Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 372, Issue 1726
  • DOI: 10.1098/rstb.2016.0214

Crystal structure of the extracellular domain of glycoprotein B from Human Cytomegalovirus
text, January 2015

Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

Isotope labeling strategies for the study of high-molecular-weight proteins by solution NMR spectroscopy
journal, July 2006

  • Tugarinov, Vitali; Kanelis, Voula; Kay, Lewis E.
  • Nature Protocols, Vol. 1, Issue 2
  • DOI: 10.1038/nprot.2006.101

The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure
journal, December 2020

Backbone-independent NMR resonance assignments of methyl probes in large proteins
journal, January 2021

  • Nerli, Santrupti; De Paula, Viviane S.; McShan, Andrew C.
  • Nature Communications, Vol. 12, Issue 1
  • DOI: 10.1038/s41467-021-20984-0

Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
journal, February 2021

Multi-functionality of a tryptophan residue conserved in substrate-binding groove of GH19 chitinases
journal, January 2021

Combined Covalent-Electrostatic Model of Hydrogen Bonding Improves Structure Prediction with Rosetta
text, January 2015

  • Jack, Snoeyink,; Tanja, Kortemme,; J., O’Meara, Matthew
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/ax5s-ky53

RosettaScripts: A Scripting Language Interface to the Rosetta Macromolecular Modeling Suite
text, January 2011

  • Paul, Murphy,; David, Baker,; Nobuyasu, Koga,
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/qh1b-9733

Modeling Symmetric Macromolecular Structures in Rosetta3
text, January 2011

  • David, Baker,; Phil, Bradley,; Andrew, Leaver-Fay,
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/t8nf-n096

A Generic Program for Multistate Protein Design
text, January 2011

  • Ron, Jacak,; Andrew, Leaver-Fay,; Benjamin, Stranges, P.
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/wvx4-nh86

PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Apollo - University of Cambridge Repository
  • DOI: 10.17863/cam.45787
    Sort by:
    [ × clear filter / sort ]

    Figures / Tables found in this record:

    Fig. 1 (p. 2)figure
    Fig. 2 (p. 3)figure
    Fig. 3 (p. 4)figure
    Fig. 4 (p. 5)figure
      [ × clear filter / sort ]
      Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.

      Similar Records in DOE PAGES and OSTI.GOV collections:

      Other research related to this record: