Unifying constraints linking protein folding and native dynamics decoded from AlphaFold
Open accessPreprint — published as 10.1103/7j2j-f8f7 · Paper page
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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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Varadi, M., Bertoni, D., Magana, P., Paramval, U., Pidruchna, I., Radhakrishnan, M., Tsenkov, M., Nair, S., Mirdita, M., Yeo, J., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkad1011 · Cited by 2,052 · cited 1× · see citing works
“Tools such as Al-phaFold 2 (AF2) [6], RosettaFold [7], and ESMFold [8] now produce near-atomic resolution predictions, while the AlphaFold Database (AFDB) contains hundreds of millions of structures across diverse organisms [9, 10].”
A structural biology community assessment of AlphaFold2 applications
Akdel, M., Pires, D. E. V., Pardo, E. P., Jänes, J., Zalevsky, A. O., Mészáros, B., Bryant, P., Good, L. L., Laskowski, R. A., Pozzati, G., et al. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00849-w · Cited by 675 · see citing works
Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation
Lee, C. Y., Hubrich, D., Varga, J. K., Schäfer, C., Welzel, M., Schumbera, E., Djokic, M., Strom, J. M., Schönfeld, J., Geist, J. L., et al. (2024) · Molecular Systems Biology · doi:10.1038/s44320-023-00005-6 · Cited by 105 · cited 1× · see citing works
“Looking ahead, integrating this framework with models of sequence variation [32, 65], protein–protein interactions [66, 67], and functional constraints (e.g., allosteric transitions and ligand binding) [68–70] A. Entropic Measures —”
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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
- openRxiv
- Published
- 2026-01-09
- Volume
- 136
- Issue
- 6
- Pages
- 068401-068401
- ISSN
- 0031-9007 (ISSN-L)
- OpenAlex
- W7124845671
- Cited by
- 5
- References
- 4
- Citations by year
- 2026: 5
- FWCI
- 10.26
- 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 of Hong Kong (22302723)
- 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, University of Chinese Academy of Sciences (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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