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Entropy, enthalpy, and evolution: Adaptive trade-offs in protein binding thermodynamics
Rosemary Georgelin1, Colin J Jackson2
1Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra, ACT 2601, Australia.
Current Opinion in Structural Biology
|June 18, 2025
Summary
Protein evolution is shaped by binding thermodynamics, specifically enthalpy-entropy trade-offs. Ancient proteins favored flexible binding, while modern proteins utilize specific, enthalpic interactions for adaptation.
Area of Science:
- Biochemistry
- Evolutionary Biology
- Structural Biology
Background:
- Protein-ligand interactions are fundamental to biological processes.
- Thermodynamics governs protein-ligand binding, influencing protein evolution.
- The evolution of binding thermodynamics, especially enthalpy-entropy trade-offs, is not well understood.
Purpose of the Study:
- To review experimental and computational findings on the evolution of protein binding thermodynamics.
- To explore how enthalpy-entropy trade-offs influence protein structure and function over evolutionary time.
- To hypothesize about the distinct thermodynamic binding strategies of ancient versus modern proteins.
Main Methods:
- Comparative analysis of experimental and computational data on protein-ligand interactions.
- Review of evolutionary trajectories, including ancestral sequence reconstruction and viral evolution.
- Synthesis of existing research from an evolutionary perspective.
Main Results:
- Ancient proteins likely evolved flexible, entropically favored binding modes.
- Modern proteins increasingly exhibit enthalpically driven specificity.
- Thermodynamic trade-offs facilitate protein adaptation to diverse functions throughout evolution.
Conclusions:
- Binding thermodynamics are crucial drivers of protein evolution, influencing structure and function.
- Understanding these thermodynamic principles can inform protein engineering strategies.
- An evolutionary perspective reveals the dynamic nature of protein-ligand binding thermodynamics.
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