The DOI matches its Crossref record; 306 of the 306 references it cites were found in a registry or an index.
Understanding a protein fold: The physics, chemistry, and biology of α-helical coiled coils
Open accessAbstract
Protein science is being transformed by powerful computational methods for structure prediction and design: AlphaFold2 can predict many natural protein structures from sequence, and other AI methods are enabling the de novo design of new structures.This raises a question: how much do we understand the underlying sequence-to-structure/function relationships being captured by these methods?This perspective presents our current understanding of one class of protein assembly, the α-helical coiled coils.At first sight, these are straightforward: sequence repeats of hydrophobic (h) and polar (p) residues, (hpphppp) n , direct the folding and assembly of amphipathic α helices into bundles.However, many different bundles are possible: they can have two or more helices (different oligomers); the helices can have parallel, antiparallel, or mixed arrangements (different topologies); and the helical sequences can be the same (homomers) or different (heteromers).Thus, sequence-to-structure relationships must be present within the hpphppp repeats to distinguish these states.I discuss the current understanding of this problem at three levels: first, physics gives a parametric framework to generate the many possible coiled-coil backbone structures.Second, chemistry provides a means to explore and deliver sequence-to-structure relationships.Third, biology shows how coiled coils are adapted and functionalized in nature, inspiring applications of coiled coils in synthetic biology.I argue that the chemistry is largely understood; the physics is partly solved, though the considerable challenge of predicting even relative stabilities of different coiled-coil states remains; but there is much more to explore in the biology and synthetic biology of coiled coils.
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“The free energy landscape of coiled coils is complex, consisting of multiple local, energetically close minima.32,33”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [32]
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“For these reasons, achieving quantitative predictions of coiled-coil stability by calculating the free energy of oligomerization has been deemed one of the outstanding challenges in coiled coil research.32”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [32]
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“However, the computational design of multistate coiled-coil protein assemblies is challenging, as it requires accurate estimates of the free energy differences between multiple alternative coiled-coil conformations.”
From Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints (2025) · cites this paper as [32]
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Highly accurate protein structure prediction with AlphaFold
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“Moreover, I am sure that this will grow with the application of AlphaFold2 to entire proteomes and the development of AlphaFold2 Multimer (3, 4, 242).”
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“A particularly interesting example is the H protein from bacteriophage Φ X174, which forms a tube that is essential for the virus to infect E. coli and is believed to transfer the viral ssDNA across the host periplasm.”
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“Moreover, I am sure that this will grow with the application of AlphaFold2 to entire proteomes and the development of AlphaFold2 Multimer (3, 4, 242).”
Accurate prediction of protein structures and interactions using a 3-track network
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InfluentialThe Leucine Zipper: A Hypothetical Structure Common to a New Class of DNA Binding Proteins
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Highly accurate protein structure prediction for the human proteome
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“Moreover, I am sure that this will grow with the application of AlphaFold2 to entire proteomes and the development of AlphaFold2 Multimer (3, 4, 242).”
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“The hemagglutinin story became more interesting as it unraveled; for example, revealing a spring-loaded switch to a longer trimeric CC leading to virus-host membrane fusion, Figure 1 D (46, 47), and targets for drug design (48, 49).”
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Cited by
Sorted by citations
De novo protein design—From new structures to programmable functions
Kortemme, T. (2024) · Cell · doi:10.1016/j.cell.2023.12.028 · Cited by 383
“Generalizing this idea, a systematic exploration of alpha-helical coiled-coils led to the design of novel architectures and development of principles to exploit these architectures for diverse functions 55 .”
An atlas of protein homo-oligomerization across domains of life
Schweke, H., Pacesa, M., Levin, T., Goverde, C. A., Kumar, P., Duhoo, Y., Dornfeld, L. J., Dubreuil, B., Georgeon, S., Ovchinnikov, S., et al. (2024) · Cell · doi:10.1016/j.cell.2024.01.022 · Cited by 144
Self-citationBlueprinting extendable nanomaterials with standardized protein blocks
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“There is a rich history of designing coiled coils using simple geometric principles; this extensibility and designability have made them widely used constituents of designed protein materials 15 .”
Coiled-coil domains are sufficient to drive liquid-liquid phase separation in protein models
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Diversity of Bioinspired Hydrogels: From Structure to Applications
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Background
Metadata
- Authors
- Woolfson, D. N.
- Affiliations
- University of Bristol (GB)
- Corresponding author
- Woolfson, Derek N.
- ORCID
- Woolfson, Derek N.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2023-04
- Volume
- 299
- Issue
- 4
- Pages
- 104579
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC10124910
- OpenAlex
- W4323276421
- Semantic Scholar
- e4a88b334ce7fa373dec876f2a178f521ccd9503
- Cited by
- 106
- References
- 292
- Citations by year
- 2026: 24 · 2025: 39 · 2024: 29 · 2023: 14
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (submittedVersion, cc-by-nc-nd)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/S002820/1, BB/V004220/1, BB/V006231/1)
- Royal Society (WM140008)
- University of Bristol
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- alpha-helical coiled coil, coiled-coil stability, synthetic biology, protein design, protein folding
- MeSH terms
- Protein Domains, Protein Conformation, alpha-Helical, Biology, Physics, Proteins, Protein Folding
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