From Levinthal to pathways to funnels
Abstract
While the classical view of protein folding kinetics relies on phenomenological models, and regards folding intermediates in a structural way, the new view emphasizes the ensemble nature of protein conformations. Although folding has sometimes been regarded as a linear sequence of events, the new view sees folding as parallel microscopic multi-pathway diffusion-like processes. While the classical view invoked pathways to solve the problem of searching for the needle in the haystack, the pathway idea was then seen as conflicting with Anfinsen's experiments showing that folding is pathway-independent (Levinthal's paradox). In contrast, the new view sees no inherent paradox because it eliminates the pathway idea: folding can funnel to a single stable state by multiple routes in conformational space. The general energy landscape picture provides a conceptual framework for understanding both two-state and multi-state folding kinetics. Better tests of these ideas will come when new experiments become available for measuring not just averages of structural observables, but also correlations among their fluctuations. At that point we hope to learn much more about the real shapes of protein folding landscapes.
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In solution, protein conformational fluctuations cause even stable proteins to form ensembles of highly populated substates with thermodynamic population distributions.
“Conformational fluctuations of proteins in solution,11 as revealed mostly by nuclear magnetic resonance (NMR) experiments and computations, make even stable proteins exist as conformational ensembles with highly populated substates whose populations follow thermodynamic distributions.12–16”
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 [14]
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- Authors
- Dill, K. A., & Chan, H. S.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Nature Structural & Molecular Biology
- Published
- 1997-01
- Volume
- 4
- Issue
- 1
- Pages
- 10-19
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2014095962
- Cited by
- 2,293
- References
- 111
- Citations by year
- 2026: 31 · 2025: 40 · 2024: 40 · 2023: 41 · 2022: 46 · 2021: 61 · 2020: 62 · 2019: 51 · 2018: 68 · 2017: 84 · 2016: 86 · 2015: 74 · 2014: 94 · 2013: 104 · 2012: 91
- FWCI
- 7.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Keywords
- protein folding kinetics, Levinthal's paradox, folding pathways, folding funnel, energy landscape, conformational ensembles, folding intermediates, two-state folding, conformational space
- MeSH terms
- Kinetics, Models, Chemical, Protein Folding
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