Folding and binding cascades: Dynamic landscapes and population shifts
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Whereas previously we have successfully utilized the folding funnels concept to rationalize binding mechanisms (Ma B, Kumar S, Tsai CJ, Nussinov R, 1999, Protein Eng 12:713–720) and to describe binding (Tsai CJ, Kumar S, Ma B, Nussinov R, 1999, Protein Sci 8:1181–1190), here we further extend the concept of folding funnels, illustrating its utility in explaining enzyme pathways, multimolecular associations, and allostery. This extension is based on the recognition that funnels are not stationary; rather, they are dynamic, depending on the physical or binding conditions (Tsai CJ, Ma B, Nussinov R, 1999, Proc Natl Acad Sci USA 96:9970–9972). Different binding states change the surrounding environment of proteins. The changed environment is in turn expressed in shifted energy landscapes, with different shapes and distributions of populations of conformers. Hence, the function of a protein and its properties are not only decided by the static folded three‐dimensional structure; they are determined by the distribution of its conformational substates, and in particular, by the redistributions of the populations under different environments. That is, protein function derives from its dynamic energy landscape, caused by changes in its surroundings.
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Population shifts within dynamic distributions provide the link to function and life.
“It is the dynamic change in the distributions – via population shifts – that portrays and captures the linkage to function and life.89”
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 [89]
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 [89]
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 [89]
Biomolecules are dynamical objects that are always interconverting between structures with varying energies, and this is the origin of allosteric mechanisms.
“biomolecules are dynamical objects that are always interconverting between a variety of structures with varying energies,166 and that this is the origin of allosteric mechanisms.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [169]
The conformational selection mechanism theorizes that the energy surface hosts a very large number of conformations, the best-fitting one is selected, with subsequent minor induced fit optimization largely by side chains.
“In contrast, the conformational selection mechanism167−169,185 theorizes that the energy surface hosts a very large number of conformations, and the one that fits best is selected, with subsequent minor induced fit optimization, largely by side chains.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [169]
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Self-citation
- Authors
- Kumar, S., Ma, B., Tsai, C., Sinha, N., & 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
- 2000-01
- Volume
- 9
- Issue
- 1
- Pages
- 10-19
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC2144430
- OpenAlex
- W2147466870
- Cited by
- 595
- References
- 59
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 7 · 2023: 11 · 2022: 11 · 2021: 28 · 2020: 16 · 2019: 23 · 2018: 17 · 2017: 16 · 2016: 30 · 2015: 23 · 2014: 36 · 2013: 46 · 2012: 39
- FWCI
- 1.20
- 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
- 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 › Protein Interaction Studies and Fluorescence Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- folding funnel, protein folding, protein binding, conformational populations, protein function, allosteric regulation, protein environment
- MeSH terms
- Models, Molecular, Protein Binding, Protein Conformation, Protein Folding
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