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Updated: Jun 13, 2026
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Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions
Published on: January 26, 2024
The structural and energetic basis for high selectivity in a high-affinity protein-protein interaction
Nicola A G Meenan1, Amit Sharma, Sarel J Fleishman
1Department of Biology, P.O. Box 373, University of York, York, YO10 5YW, United Kingdom.
Summary
Understanding protein-protein interaction selectivity is key. This study reveals how weak, noncognate complexes, like colicin E9 endonuclease (E9 DNase) and immunity protein 2 (Im2), can be weakened by "frustration" yet primed for high-affinity binding through minimal mutations.
Area of Science:
- Structural Biology
- Biochemistry
- Evolutionary Biology
Background:
- High-affinity protein-protein interactions are vital for cell survival.
- Evolutionary paradox: how selectivity evolves without lethal loss of binding.
- Understanding weak, noncognate complexes is crucial for selectivity insights.
Purpose of the Study:
- To investigate the structural basis of selectivity in protein-protein interactions.
- To characterize the weak, noncognate complex between colicin E9 endonuclease (E9 DNase) and immunity protein 2 (Im2).
- To elucidate the evolutionary mechanisms driving high-affinity binding.
Main Methods:
- NMR-based docking guided disulfide-trapping strategy.
- X-ray crystallography at 1.77 Å resolution.
- Computational alanine scanning of interfacial residues.
Main Results:
- Determined the crystal structure of the E9 DNase-Im2 noncognate complex.
- Identified an entirely noncovalent interface weakened by 'frustration' due to strong binding forces.
- Highlighted the role of loop regions and buried water molecules in selectivity.
Conclusions:
- Weakened noncognate complexes are primed for high-affinity binding via economical mutations.
- Supports dual-recognition mechanisms in colicin DNase-Im protein interactions.
- Provides insights into the evolution of binding selectivity.
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