Cited by 5Protein Structure and DynamicsRNA and protein synthesis mechanismsEnzyme Structure and Function

Unifying Constraints Linking Protein Folding and Native Dynamics Decoded from AlphaFold

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Zhang, Zecheng, Ren, Weitong, Xie, Liangxu, Zheng, Yuxiang, Guan, Xingyue, Wang, Jun, Li, Wenfei, Tang, Qian-Yuan·2026·Physical Review Letters

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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)
Venue
Physical Review Letters
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
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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