High thermodynamic stability of parametrically designed helical bundles
Open accessAbstract
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.
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The majority of de novo designed coiled coils are hyperstable, with melting points exceeding 100 °C.
“However, the majority of de novo designed coiled coils are hyperstable, with melting points exceeding 100 °C.11,12”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [11]
The paper reports a designed helical bundle with no melting transition up to 130°C, supporting the existence of exceptionally stable designs (section labelled Abstract; page unavailable). It does not support the claim that a majority have melting points above 100°C: it identifies only two of nine tested designs as hyperstable, and reports stability only up to 95°C for several others. (LLM, conf=0.87)
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Self-citation
- Authors
- Huang, P.-S., Oberdorfer, G., Xu, C., Pei, X. Y., Nannenga, B. L., Rogers, J. M., DiMaio, F., Gonen, T., Luisi, B., & Baker, D.
- Affiliations
- University of Washington (US)
- University of Graz (AT)
- University of Cambridge (GB)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Huang, Po-Ssu
- Oberdorfer, Gustav
- Xu, Chunfu
- Baker, David
- ORCID
- Venue
- Science
- Published
- 2014-10-24
- Volume
- 346
- Issue
- 6208
- Pages
- 481-485
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4612401
- OpenAlex
- W1976603396
- Cited by
- 277
- References
- 32
- Citations by year
- 2026: 17 · 2025: 17 · 2024: 16 · 2023: 22 · 2022: 24 · 2021: 28 · 2020: 23 · 2019: 29 · 2018: 15 · 2017: 30 · 2016: 37 · 2015: 17 · 2014: 2
- FWCI
- 11.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy (-AC02-05CH11231, 05CH11231, DE AC02 05CH11231, DE-AC02-)
- Wellcome Trust (076846)
- Diamond Light Source
- European Commission (332094)
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- protein design, helical bundle, coiled coil, thermodynamic stability, protein folding free energy, combinatorial designs
- MeSH terms
- Protein Denaturation, Thermodynamics, Protein Engineering, Protein Structure, Secondary, Crystallography, X-Ray, Combinatorial Chemistry Techniques
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