On the origin and highly likely completeness of single-domain protein structures
Open accessAbstract
The size and origin of the protein fold universe is of fundamental and practical importance. Analyzing randomly generated, compact sticky homopolypeptide conformations constructed in generic simplified and all-atom protein models, all have similar folds in the library of solved structures, the Protein Data Bank, and conversely, all compact, single-domain protein structures in the Protein Data Bank have structural analogues in the compact model set. Thus, both sets are highly likely complete, with the protein fold universe arising from compact conformations of hydrogen-bonded, secondary structures. Because side chains are represented by their C β atoms, these results also suggest that the observed protein folds are insensitive to the details of side-chain packing. Sequence specificity enters both in fine-tuning the structure and thermodynamically stabilizing a given fold with respect to the set of alternatives. Scanning the models against a three-dimensional active-site library, close geometric matches are frequently found. Thus, the presence of active-site-like geometries also seems to be a consequence of the packing of compact, secondary structural elements. These results have significant implications for the evolution of protein structure and function.
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The library of single domain protein structures is essentially complete.
“The key to why AF211 works is the fact the library of single domain protein structures is essentially complete.2,12,13”
From AlphaFold 2: Why It Works and Its Implications for Understanding the Relationships of Protein Sequence, Structure, and Function (2021) · cites this paper as [12]
The reason SAdLSA trained on helical proteins works for β-proteins is that the global topology of β-proteins is in the training set; the chain contour of helical proteins provides a globally correct fold for β-proteins.
“The reason that SAdLSA trained on helical proteins works for β-proteins is that the global topology of β-proteins is in the training set;2,12,13 the chain contour of helical proteins provides a globally correct fold for β-proteins.13”
From AlphaFold 2: Why It Works and Its Implications for Understanding the Relationships of Protein Sequence, Structure, and Function (2021) · cites this paper as [12]
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Self-citation
- Authors
- Zhang, Y., Hubner, I. A., Arakaki, A. K., Shakhnovich, E., & Skolnick, J.
- Affiliations
- University at Buffalo, State University of New York (US)
- Harvard University (US)
- *Center of Excellence in Bioinformatics, University at Buffalo, State University of New York, 901 Washington Street, Buffalo, NY 14203; and
- Georgia Institute of Technology (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-02-14
- Volume
- 103
- Issue
- 8
- Pages
- 2605-2610
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2121125726
- Cited by
- 197
- References
- 39
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 9 · 2022: 7 · 2021: 2 · 2020: 4 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 5 · 2015: 6 · 2014: 10 · 2013: 13 · 2012: 11
- FWCI
- 8.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institute of General Medical Sciences (GM 37408, GM068670, R01GM037408, GM-48835, R01GM048835, R01GM068670)
- 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 › RNA and protein synthesis mechanisms
- Keywords
- side-chain packing, active site geometry, protein structure evolution, Protein Data Bank
- MeSH terms
- Animals, Binding Sites, Humans, Models, Molecular, Proteins, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Folding, Evolution, Molecular, Databases, Protein
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