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

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...

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Bibliographic Details
Published inNature structural & molecular biology Vol. 25; no. 11; pp. 1028 - 1034
Main Authors Marcos, 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., Baker, David
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.11.2018
Nature Publishing Group
Subjects
631/114/470
631/45/612
631/535/878/1263
82/16
82/29
82/58
82/6
82/80
82/83
Amino Acid Sequence
Arches
Biochemistry
Biological Microscopy
Biomedical and Life Sciences
Computation
Computer applications
Computer Simulation
Design
Domains
First principles
Helices
Hydrogen Bonding
Life Sciences
Membrane Biology
Models, Molecular
NMR
Nuclear magnetic resonance
Nuclear Magnetic Resonance, Biomolecular
Protein Conformation
Protein Conformation, beta-Strand
Protein Engineering - methods
Protein Folding
Protein Stability
Protein Structure
Proteins
Proteins - chemistry
Proteins - genetics
Strands
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Summary: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. Baker, Marcos and colleagues analyze β-arches (loops connecting unpaired β-strands) and derive rules used for de novo design of a hyperthermostable jellyroll structure, with eight antiparallel β-strands forming double-stranded β-helices.
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Present address: Cyrus Biotechnology, Seattle, WA 98101, USA.
Present address: Institute of Biochemistry, Graz University of Technology, Petersgasse 12/2, 8010 Graz, Austria.
E.M. designed the research, carried out the loops structural analysis, set up the design method and performed design calculations. T.M.C. carried out design calculations, protein expression, purification and CD experiments. A.C.M. collected 4D-NMR data. T.E. performed 4D-CHAINS analysis. S.N. carried out AutoNOE-Rosetta calculations. L.C. expressed isotopically labeled proteins and performed SEC-MALS analysis. L.G.N. designed the research and carried out design calculations. A.D. and G.O. helped in protein expression and characterization. K.T. and N.G.S. supervised NMR structure determination. D.B. designed and supervised the research. E.M. and D.B. prepared the manuscript with input from all authors.
AUTHOR CONTRIBUTIONS
Present address: Amazon, Seattle, WA 98121, USA.
ISSN:1545-9993
1545-9985
DOI:10.1038/s41594-018-0141-6