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

Nat Struct Mol Biol. 2018 Nov;25(11):1028-1034. doi: 10.1038/s41594-018-0141-6. Epub 2018 Oct 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Computer Simulation
  • Hydrogen Bonding
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation
  • Protein Conformation, beta-Strand
  • Protein Engineering / methods*
  • Protein Folding
  • Protein Stability
  • Proteins / chemistry*
  • Proteins / genetics

Substances

  • Proteins