TY - JOUR
T1 - De novo design of a non-local β-sheet protein with high stability and accuracy
AU - Marcos, Enrique
AU - Chidyausiku, Tamuka M.
AU - McShan, Andrew C.
AU - Evangelidis, Thomas
AU - Nerli, Santrupti
AU - Carter, Lauren
AU - Nivón, Lucas G.
AU - Davis, Audrey
AU - Oberdorfer, Gustav
AU - Tripsianes, Konstantinos
AU - Sgourakis, Nikolaos G.
AU - Baker, David
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055985092&partnerID=8YFLogxK
U2 - 10.1038/s41594-018-0141-6
DO - 10.1038/s41594-018-0141-6
M3 - Article
C2 - 30374087
AN - SCOPUS:85055985092
SN - 1545-9993
VL - 25
SP - 1028
EP - 1034
JO - Nature Structural & Molecular Biology
JF - Nature Structural & Molecular Biology
IS - 11
ER -