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

TitleDe novo design of a non-local β-sheet protein with high stability and accuracy
Publication TypeJournal Article
Year of Publication2018
AuthorsMarcos, Enrique, Chidyausiku Tamuka M., McShan Andrew C., Evangelidis Thomas, Nerli Santrupti, Carter Lauren, Nivón Lucas G., Davis Audrey, Oberdorfer Gustav, Tripsianes Konstantinos, Sgourakis Nikolaos G., and Baker David
JournalNature structural & molecular biology
Pagination1028 - 1034
Date Published11/2018
ISBN Number1545-99851545-9993
KeywordsAmino 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/genetics

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.

Short TitleNat Struct Mol Biol