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

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

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
Volume25
Issue number11
DOIs
Publication statusPublished - 1 Nov 2018

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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