Journal
SCIENCE
Volume 346, Issue 6208, Pages 481-485Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1257481
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Funding
- Advanced Light Source (U.S. Department of Energy) [DE-AC02-05CH11231]
- Howard Hughes Medical Institute
- Defense Threat Reduction Agency
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council
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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 Delta G(fold) > 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.
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