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

ABSTRACT: ?-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-?-sheet proteins from first principles lags far behind the design of all-? or mixed-?? domains owing to their non-local nature and the tendency of exposed ?-strand edges to aggregate. Through study of loops connecting unpaired ?-strands (?-arches), we have identified a series of structural relationships between loop geometry, side chain directionality and ?-strand length that arise from hydrogen bonding and packing constraints on regular ?-sheet structures. We use these rules to de novo design jellyroll structures with double-stranded ?-helices formed by eight antiparallel ?-strands. The nuclear magnetic resonance structure of a hyperthermostable design closely matched the computational model, demonstrating accurate control over the ?-sheet structure and loop geometry. Our results open the door to the design of a broad range of non-local ?-sheet protein structures.

SUBMITTER: Marcos E 

PROVIDER: S-EPMC6219906 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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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,  ...[more]

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