Protein–protein interactions: Structurally conserved residues distinguish between binding sites and exposed protein surfaces
Open accessAbstract
Polar residue hot spots have been observed at protein–protein binding sites. Here we show that hot spots occur predominantly at the interfaces of macromolecular complexes, distinguishing binding sites from the remainder of the surface. Consequently, hot spots can be used to define binding epitopes. We further show a correspondence between energy hot spots and structurally conserved residues. The number of structurally conserved residues, particularly of high ranking energy hot spots, increases with the binding site contact size. This finding may suggest that effectively dispersing hot spots within a large contact area, rather than compactly clustering them, may be a strategy to sustain essential key interactions while still allowing certain protein flexibility at the interface. Thus, most conserved polar residues at the binding interfaces confer rigidity to minimize the entropic cost on binding, whereas surrounding residues form a flexible cushion. Furthermore, our finding that similar residue hot spots occur across different protein families suggests that affinity and specificity are not necessarily coupled: higher affinity does not directly imply greater specificity. Conservation of Trp on the protein surface indicates a highly likely binding site. To a lesser extent, conservation of Phe and Met also imply a binding site. For all three residues, there is a significant conservation in binding sites, whereas there is no conservation on the exposed surface. A hybrid strategy, mapping sequence alignment onto a single structure illustrates the possibility of binding site identification around these three residues.
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Hot spot residues at binding interfaces are rigid, which reduces the entropic cost of binding.
“Hot spot residues at binding interfaces confer rigidity to minimize the entropic cost of binding”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [496]
Residues surrounding conserved residues can form a flexible cushion.
“whereas the residues surrounding the conserved residues may form a flexible cushion.496”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [496]
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- Authors
- Ma, B., Elkayam, T., Wolfson, H., & Nussinov, R.
- Affiliations
- Tel Aviv University (IL)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-05
- Volume
- 100
- Issue
- 10
- Pages
- 5772-5777
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC156276
- OpenAlex
- W2160690759
- Cited by
- 595
- References
- 50
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 16 · 2023: 14 · 2022: 16 · 2021: 13 · 2020: 22 · 2019: 21 · 2018: 16 · 2017: 17 · 2016: 21 · 2015: 28 · 2014: 23 · 2013: 27 · 2012: 40
- FWCI
- 13.33
- 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 Institutes of Health (n01co12400-79-0-22)
- National Cancer Institute (N01CO12400, N01-CO-012400)
- 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 › Machine Learning in Bioinformatics
- Keywords
- protein-protein interaction, binding sites, binding epitope, tryptophan, phenylalanine, methionine, protein flexibility, binding site identification
- MeSH terms
- Amino Acid Sequence, Epitopes, Binding Sites, Molecular Sequence Data, Proteins, Tryptophan, Sequence Alignment, Conserved Sequence, Sequence Homology, Amino Acid
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