Structured disorder and conformational selection
Abstract
Traditionally, molecular disorder has been viewed as local or global instability. Molecules or regions displaying disorder have been considered inherently unstructured. The term has been routinely applied to cases for which no atomic coordinates can be derived from crystallized molecules. Yet, even when it appears that the molecules are disordered, prevailing conformations exist, with population times higher than those of all alternate conformations. Disordered molecules are the outcome of rugged energy landscapes away from the native state around the bottom of the funnel. Ruggedness has a biological function, creating a distribution of structured conformers that bind via conformational selection, driving association and multimolecular complex formation, whether chain‐linked in folding or unlinked in binding. We classify disordered molecules into two types. The first type possesses a hydrophobic core. Here, even if the native conformation is unstable, it still has a large enough population time, enabling its experimental detection. In the second type, no such hydrophobic core exists. Hence, the native conformations of molecules belonging to this category have shorter population times, hindering their experimental detection. Although there is a continuum of distribution of hydrophobic cores in proteins, an empirical, statistically based hydrophobicity function may be used as a guideline for distinguishing the two disordered molecule types. Furthermore, the two types relate to steps in the protein folding reaction. With respect to protein design, this leads us to propose that engineering‐optimized specific electrostatic interactions to avoid electrostatic repulsion would reduce the type I disordered state, driving the molten globule (MG) → native (N) state. In contrast, for overcoming the type II disordered state, in addition to specific interactions, a stronger hydrophobic core is also indicated, leading to the denatured → MG → N state. Proteins 2001;44:418–427. © 2001 Wiley‐Liss, Inc.
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Analysis of tau protein conformational ensembles supports structured disorder and conformational selection as functional mechanism for IDPs.
“The results of the analysis of the conformational ensembles of the tau proteins support the view of structured disorder and conformational selection as functional mechanism for IDPs.377”
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 [377]
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- Authors
- Tsai, C., Ma, B., Sham, Y. Y., Kumar, S., & Nussinov, R.
- Affiliations
- National Cancer Institute (US)
- Frederick National Laboratory for Cancer Research (US)
- Tel Aviv University (IL)
- Corresponding author
- Nussinov, Ruth
- Venue
- Proteins: Structure, Function, and Bioinformatics
- Publisher
- Wiley
- Published
- 2001-07-11
- Volume
- 44
- Issue
- 4
- Pages
- 418-427
- ISSN
- 0887-3585 (ISSN-L)
- 1097-0134
- OpenAlex
- W2075702662
- Cited by
- 202
- References
- 52
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 11 · 2017: 13 · 2016: 8 · 2015: 12 · 2014: 15 · 2013: 18 · 2012: 18
- FWCI
- 0.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Proteins Structure Function and Bioinformatics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- Israel Science Foundation
- Tel Aviv University
- National Institutes of Health (n01co056000-057)
- National Cancer Institute (N01 CO 56000)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- intrinsically disordered proteins, conformational selection, rugged energy landscape, hydrophobic core, protein folding, molten globule, protein design, electrostatic interactions, protein binding, protein complex formation
- MeSH terms
- Enzyme Stability, Models, Molecular, Protein Conformation, Protein Denaturation, Proteins, Structure-Activity Relationship, Thermodynamics, Protein Folding, Protein Renaturation
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