Can three-dimensional contacts in protein structures be predicted by analysis of correlated mutations?
Abstract
A method has been developed to detect pairs of positions with correlated mutations in protein multiple sequence alignments. The method is based on reconstruction of the phylogenetic tree for a set of sequences and statistical analysis of the distribution of mutations in the branches of the tree. The database of homology-derived protein structures (HSSP) is used as the source of multiple sequence alignments for proteins of known three-dimensional structure. We analyse pairs of positions with correlated mutations in 67 protein families and show quantitatively that the presence of such positions is a typical feature of protein families. A significant but weak tendency is observed for correlated residue pairs to be close in the three-dimensional structure. With further improvements, methods of this type may be useful for the prediction of residue--residue contacts and subsequent prediction of protein structure using distance geometry algorithms. In conclusion, we suggest a new experimental approach to protein structure determination in which selection of functional mutants after random mutagenesis and analysis of correlated mutations provide sufficient proximity constraints for calculation of the protein fold.
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One of the major insights leveraged by AlphaFold comes from the use of evolutionary covariations that can be extracted from large-scale multiple sequence alignments.
“One of the major insights leveraged by AlphaFold 1,2 comes from the use of evolutionary covariations that can be extracted from large-scale multiple sequence alignments.[49][50][51][52][53][54]”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [49]
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- Authors
- Shindyalov, I. N., Kolchanov, N. A., & Sander, C.
- Affiliations
- Russian Academy of Sciences (RU)
- European Molecular Biology Laboratory (DE)
- Venue
- "Protein Engineering, Design and Selection"
- Publisher
- Oxford University Press (OUP)
- Published
- 1994
- Volume
- 7
- Issue
- 3
- Pages
- 349-358
- ISSN
- 0269-2139 (ISSN-L)
- 1741-0126
- 1741-0134
- OpenAlex
- W2033806446
- Cited by
- 297
- References
- 0
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 10 · 2021: 11 · 2020: 5 · 2019: 7 · 2018: 16 · 2017: 5 · 2016: 7 · 2015: 11 · 2014: 23 · 2013: 8 · 2012: 9
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Protein Engineering Design and Selection (publishedVersion)
- PubMed (publishedVersion)
- 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
- correlated mutations, residue-residue contacts, protein structure prediction, phylogenetic inference, multiple sequence alignment, protein families, distance geometry, random mutagenesis
- MeSH terms
- Amino Acid Sequence, Amino Acids, Chemistry, Physical, Cytochrome c Group, DNA-Binding Proteins, Biological Evolution, Molecular Sequence Data, Mutation, Proteins, Repressor Proteins, Trypsin, Viral Proteins, Molecular Structure, Mutagenesis, Sequence Alignment, Protein Structure, Secondary, Viral Regulatory and Accessory Proteins, Chemical Phenomena
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