De novo design of a non-local β-sheet protein with high stability and accuracy

Enrique Marcos, Tamuka M. Chidyausiku, Andrew C. McShan, Thomas Evangelidis, Santrupti Nerli, Lauren Carter, Lucas G. Nivón, Audrey Davis, Gustav Oberdorfer, Konstantinos Tripsianes, Nikolaos G. Sgourakis, David Baker

Research output: Contribution to journalArticleResearchpeer-review


β-sheet proteins carry out critical functions in biology, and hence are attractive scaffolds for computational protein design. Despite this potential, de novo design of all-β-sheet proteins from first principles lags far behind the design of all-α or mixed-αβ domains owing to their non-local nature and the tendency of exposed β-strand edges to aggregate. Through study of loops connecting unpaired β-strands (β-arches), we have identified a series of structural relationships between loop geometry, side chain directionality and β-strand length that arise from hydrogen bonding and packing constraints on regular β-sheet structures. We use these rules to de novo design jellyroll structures with double-stranded β-helices formed by eight antiparallel β-strands. The nuclear magnetic resonance structure of a hyperthermostable design closely matched the computational model, demonstrating accurate control over the β-sheet structure and loop geometry. Our results open the door to the design of a broad range of non-local β-sheet protein structures.

Original languageEnglish
Pages (from-to)1028-1034
Number of pages7
JournalNature Structural and Molecular Biology
Issue number11
Publication statusPublished - 1 Nov 2018

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Marcos, E., Chidyausiku, T. M., McShan, A. C., Evangelidis, T., Nerli, S., Carter, L., ... Baker, D. (2018). De novo design of a non-local β-sheet protein with high stability and accuracy. Nature Structural and Molecular Biology, 25(11), 1028-1034.