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Topological Links in Predicted Protein Complex Structures Reveal Limitations of AlphaFold
Open accessPreprint — published as 10.1038/s42003-023-05489-4
Abstract
AlphaFold is making great progress in protein structure prediction, not only for single-chain proteins but also for multi-chain protein complexes. When using AlphaFold-Multimer to predict protein–protein complexes, we observed some unusual structures in which chains are looped around each other to form topologically intertwining links at the interface. To our knowledge, such topological links are never observed in the experimental structures deposited in the Protein Data Bank (PDB). Although it is well known and has been well studied that protein structures may have topologically complex shapes such as knots and links, existing methods are hampered by the chain closure problem and show poor performance in identifying topologically linked structures in protein–protein complexes. Therefore, we address the chain closure problem by using sliding windows from a local perspective and propose an algorithm to measure the topological–geometric features that can be used to identify topologically linked structures. An application of the method to AlphaFold-Multimer-predicted protein complex structures finds that approximately 0.7% of the predicted structures contain topological links. The method presented in this work will facilitate the computational study of protein–protein interactions and help further improve the structural prediction of multi-chain protein complexes.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Hou, Y., Xie, T., He, L., Tao, L., & Huang, J.
- Affiliations
- Westlake University (CN)
- Corresponding author
- Huang, Jing
- Venue
- Communications Biology
- Publisher
- openRxiv
- Published
- 2022-09-16
- Volume
- 6
- Issue
- 1
- Pages
- 1098-1098
- ISSN
- 2399-3642 (ISSN-L)
- PMC
- PMC10613300
- OpenAlex
- W4388001385
- Cited by
- 21
- References
- 1
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 8 · 2023: 1
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Communications Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Westlake University
- National Natural Science Foundation of China (LR19B030001, 32171247, 21803057, 31970129)
- Natural Science Foundation of Zhejiang Province (LQ23C050002, . LR20C010001, LR19B030001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Mathematics › Geometry and Topology › Geometric and Algebraic Topology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- protein-protein complex, AlphaFold-Multimer, protein structure prediction, protein knots, protein-protein interaction, sliding window algorithm
- MeSH terms
- Algorithms, Proteins
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