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Science. 2014 Oct 24;346(6208):481-485. doi: 10.1126/science.1257481.

High thermodynamic stability of parametrically designed helical bundles.

Author information

1
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
2
Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
3
Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50/3, 8010-Graz, Austria.
4
Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
5
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
6
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
7
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
#
Contributed equally

Abstract

We describe a procedure for designing proteins with backbones produced by varying the parameters in the Crick coiled coil-generating equations. Combinatorial design calculations identify low-energy sequences for alternative helix supercoil arrangements, and the helices in the lowest-energy arrangements are connected by loop building. We design an antiparallel monomeric untwisted three-helix bundle with 80-residue helices, an antiparallel monomeric right-handed four-helix bundle, and a pentameric parallel left-handed five-helix bundle. The designed proteins are extremely stable (extrapolated ΔGfold > 60 kilocalories per mole), and their crystal structures are close to those of the design models with nearly identical core packing between the helices. The approach enables the custom design of hyperstable proteins with fine-tuned geometries for a wide range of applications.

PMID:
25342806
PMCID:
PMC4612401
DOI:
10.1126/science.1257481
[Indexed for MEDLINE]
Free PMC Article

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