Unifying Constraints Linking Protein Folding and Native Dynamics Decoded from AlphaFold
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Abstract
The interplay between protein folding and native dynamics remains a central question in biophysics. Analyzing an extensive set of AlphaFold-predicted structures, we uncover a robust relationship between folding topology (contact order) and native dynamics (fluctuation entropy), showing that long-range contacts that slow folding also restrict conformational flexibility across protein sizes and taxonomic groups. Scaling analysis reveals that this relationship, together with its chain-length dependence, is consistent with power-law-like trends, reflecting common organizing constraints of protein architecture. Across species, increasing organismal complexity is associated with proteome-wide shifts toward lower contact order and higher fluctuation entropy. Together, evidence from folding, stability, and functional dynamics converges on unifying constraints, revealing an intrinsic physical organizing principle captured by AI models.
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- Authors
- Zhang, Z., Ren, W., Xie, L., Zheng, Y., Guan, X., Wang, J., Li, W., & Tang, Q.-Y.
- Affiliations
- Hong Kong Baptist University (HK)
- University of Chinese Academy of Sciences (CN)
- Jiangsu University of Technology (CN)
- Nanjing University (CN)
- ORCID
- Venue
- Physical Review Letters
- Publisher
- American Physical Society (APS)
- Published
- 2026-02-09
- Volume
- 136
- Issue
- 6
- Pages
- 068401-068401
- ISSN
- 0031-9007 (ISSN-L)
- 1079-7114
- OpenAlex
- W7124845671
- Cited by
- 5
- References
- 92
- Citations by year
- 2026: 5
- FWCI
- 10.46
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Physical Review Letters (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Research Grants Council, University Grants Committee (22302723)
- National Natural Science Foundation of China (12305052, 12574224, 12347102, 22003020)
- Hong Kong Baptist University (RC-FNRA-IG/22-23/SCI/03)
- Basic Research Program of Jiangsu Province (BK20253050)
- Wenzhou Institute of Biomaterials and Engineering (WIUCASQD2023015)
- 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
- protein folding, contact order, long-range contacts, conformational flexibility, protein architecture, power-law scaling, chain length dependence, organismal complexity, protein stability, protein function, AlphaFold predictions
- MeSH terms
- Models, Chemical, Models, Molecular, Protein Conformation, Proteins, Protein Folding, Entropy
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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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