Cited by 519Protein Structure and DynamicsEnzyme Structure and FunctionProtein Interaction Studies and Fluorescence Analysis

Hot Regions in Protein–Protein Interactions: The Organization and Contribution of Structurally Conserved Hot Spot Residues

Keskin, Ozlem, Ma, Buyong, Nussinov, Ruth·2005·Journal of Molecular Biology

Abstract

Structurally conserved residues at protein-protein interfaces correlate with the experimental alanine-scanning hot spots. Here, we investigate the organization of these conserved, computational hot spots and their contribution to the stability of protein associations. We find that computational hot spots are not homogeneously distributed along the protein interfaces; rather they are clustered within locally tightly packed regions. Within the dense clusters, they form a network of interactions and consequently their contributions to the stability of the complex are cooperative; however the contributions of independent clusters are additive. This suggests that the binding free energy is not a simple summation of the single hot spot residue contributions. As expected, around the hot spot residues we observe moderately conserved residues, further highlighting the crucial role of the conserved interactions in the local densely packed environment. The conserved occurrence of these organizations suggests that they are advantageous for protein-protein associations. Interestingly, the total number of hydrogen bonds and salt bridges contributed by hot spots is as expected. Thus, H-bond forming residues may use a "hot spot for water exclusion" mechanism. Since conserved residues are located within highly packed regions, water molecules are easily removed upon binding, strengthening electrostatic contributions of charge-charge interactions. Hence, the picture that emerges is that protein-protein associations are optimized locally, with the clustered, networked, highly packed structurally conserved residues contributing dominantly and cooperatively to the stability of the complex. When addressing the crucial question of "what are the preferred ways of proteins to associate", these findings point toward a critical involvement of hot regions in protein-protein interactions.

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Crossref · 10.1016/j.jmb.2004.10.077

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Authors
Keskin, O., Ma, B., & Nussinov, R.
Affiliations
National Institutes of Health (US)
Corresponding author
Nussinov, Ruth
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2005-02
Volume
345
Issue
5
Pages
1281-1294
ISSN
0022-2836 (ISSN-L)
OpenAlex
W2115156437
Cited by
519
References
66
Citations by year
2026: 11 · 2025: 12 · 2024: 20 · 2023: 14 · 2022: 18 · 2021: 24 · 2020: 11 · 2019: 17 · 2018: 29 · 2017: 22 · 2016: 25 · 2015: 27 · 2014: 21 · 2013: 34 · 2012: 29
FWCI
7.41
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (n01co12400-79-0-22)
  • National Cancer Institute (N01CO12400)
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 › Protein Interaction Studies and Fluorescence Analysis
Keywords
protein-protein interaction, hot spot residues, protein-protein interfaces, binding free energy, cooperative binding, hydrogen bonding, salt bridges, water exclusion, protein complex stability, alanine scanning
MeSH terms
Binding Sites, Hydrogen Bonding, Models, Molecular, Protein Binding, Protein Conformation, Proteins, Conserved Sequence, Protein Folding, Structural Homology, Protein, Static Electricity

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