Folding funnels, binding funnels, and protein function
Open accessAbstract
Folding funnels have been the focus of considerable attention during the last few years. These have mostly been discussed in the general context of the theory of protein folding. Here we extend the utility of the concept of folding funnels, relating them to biological mechanisms and function. In particular, here we describe the shape of the funnels in light of protein synthesis and folding; flexibility, conformational diversity, and binding mechanisms; and the associated binding funnels, illustrating the multiple routes and the range of complexed conformers. Specifically, the walls of the folding funnels, their crevices, and bumps are related to the complexity of protein folding, and hence to sequential vs. nonsequential folding. Whereas the former is more frequently observed in eukaryotic proteins, where the rate of protein synthesis is slower, the latter is more frequent in prokaryotes, with faster translation rates. The bottoms of the funnels reflect the extent of the flexibility of the proteins. Rugged floors imply a range of conformational isomers, which may be close on the energy landscape. Rather than undergoing an induced fit binding mechanism, the conformational ensembles around the rugged bottoms argue that the conformers, which are most complementary to the ligand, will bind to it with the equilibrium shifting in their favor. Furthermore, depending on the extent of the ruggedness, or of the smoothness with only a few minima, we may infer nonspecific, broad range vs. specific binding. In particular, folding and binding are similar processes, with similar underlying principles. Hence, the shape of the folding funnel of the monomer enables making reasonable guesses regarding the shape of the corresponding binding funnel. Proteins having a broad range of binding, such as proteolytic enzymes or relatively nonspecific endonucleases, may be expected to have not only rugged floors in their folding funnels, but their binding funnels will also behave similarly, with a range of complexed conformations. Hence, knowledge of the shape of the folding funnels is biologically very useful. The converse also holds: If kinetic and thermodynamic data are available, hints regarding the role of the protein and its binding selectivity may be obtained. Thus, the utility of the concept of the funnel carries over to the origin of the protein and to its function.
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The conformational selection and population shift model provides a more realistic description of molecular mechanism considering ensemble nature.
“The ‘conformational selection and population shift’ model87–89,134 provides a more realistic description of the molecular mechanism considering the ensemble nature of protein molecules.”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [88]
During binding, higher energy (lower population) conformers most complementary to pre-existing ligand conformations can be selected, shifting equilibrium toward them.
“During binding, higher energy (lower population) conformers which are most complementary to some pre-existing ligand conformations can be selected and the equilibrium shifts toward these conformers.87–89,134”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [88]
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- Authors
- Tsai, C., Kumar, S., Ma, B., & Nussinov, R.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Tel Aviv University (IL)
- Corresponding author
- Nussinov, Ruth
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 1999-01
- Volume
- 8
- Issue
- 6
- Pages
- 1181-1190
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC2144348
- OpenAlex
- W2113030357
- Cited by
- 648
- References
- 67
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 14 · 2023: 15 · 2022: 19 · 2021: 27 · 2020: 26 · 2019: 24 · 2018: 20 · 2017: 20 · 2016: 29 · 2015: 22 · 2014: 29 · 2013: 66 · 2012: 37
- FWCI
- 1.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Protein Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- Israel Science Foundation
- Tel Aviv University
- National Institutes of Health (n01co056000-057, NO1-CO-56000, CO-56000)
- National Cancer Institute (N01 CO 56000, NO1CO56000)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- folding funnel, protein folding, protein-ligand binding, conformational heterogeneity, protein flexibility, energy landscape, induced fit, non-specific binding, protein synthesis rate, protein function, protein origin, proteolytic enzymes, endonuclease
- MeSH terms
- Kinetics, Protein Conformation, Proteins, Thermodynamics, Protein Folding
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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