Structural space of protein–protein interfaces is degenerate, close to complete, and highly connected
Open accessAbstract
At the heart of protein–protein interactions are protein–protein interfaces where the direct physical interactions occur. By developing and applying an efficient structural alignment method, we study the structural similarity of representative protein–protein interfaces involving interactions between dimers. Even without structural similarity between individual monomers that form dimeric complexes, ∼90% of native interfaces have a close structural neighbor with similar backbone C α geometry and interfacial contact pattern. About 80% of the interfaces form a dense network, where any two interfaces are structurally related using a transitive set of at most seven intermediate interfaces. The degeneracy of interface space is largely due to the packing of compact, hydrogen-bonded secondary structure elements. This packing generates relatively flat interacting surfaces whose geometries are highly degenerate. Comparative study of artificial and native interfaces argues that the library of protein interfaces is close to complete and comprised of roughly 1,000 distinct interface types. In contrast, the number of possible quaternary structures of dimers is estimated to be about 10 4 times larger; thus, an experimentally determined database of all representative quaternary structures is not likely in the near future. Nevertheless, one could in principle exploit the completeness of protein interfaces to predict most dimeric quaternary structures. Finally, our results provide a structural explanation for the prevalence of promiscuous protein interactions. By side-chain packing adjustments, we illustrate how multiprotein specificity can be attained at a promiscuous interface.
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The structural space of protein-protein interfaces is quite small.
“the structural space of protein-protein interfaces, the regions where direct physical contacts are found between protein partners forming a complex, is quite small6.”
From AF2Complex predicts direct physical interactions in multimeric proteins with deep learning (2022) · cites this paper as [6]
The structural space of protein-protein interfaces is small (<1000 structurally distinct interfaces), with nothing special about protein-protein interfaces.
“In practice, the structural space of protein–protein interfaces is small (<1000 structurally distinct interfaces),41,42 with nothing special about protein–protein interfaces.43”
From AlphaFold 2: Why It Works and Its Implications for Understanding the Relationships of Protein Sequence, Structure, and Function (2021) · cites this paper as [41]
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- Authors
- Gao, M., & Skolnick, J.
- Affiliations
- Georgia Institute of Technology (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-12-13
- Volume
- 107
- Issue
- 52
- Pages
- 22517-22522
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3012513
- OpenAlex
- W1969327849
- Cited by
- 139
- References
- 33
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 9 · 2023: 5 · 2022: 8 · 2021: 8 · 2020: 10 · 2019: 7 · 2018: 5 · 2017: 9 · 2016: 9 · 2015: 12 · 2014: 14 · 2013: 14 · 2012: 14
- FWCI
- 4.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM-48835, R01GM048835)
- 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 › Biochemical and Structural Characterization
- Keywords
- protein-protein interfaces, protein-protein interaction, dimeric complexes, structural alignment, quaternary structure, side-chain packing
- MeSH terms
- Algorithms, Hydrogen Bonding, Models, Molecular, Protein Binding, Proteins, Software, Protein Structure, Secondary, Protein Structure, Tertiary, Computational Biology, Protein Structure, Quaternary, Databases, Protein, Protein Multimerization
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