Entropy, enthalpy, and evolution: Adaptive trade-offs in protein binding thermodynamics

Proteins are central to biological complexity as their ligand binding processes, shaped by thermodynamics, have driven evolutionary adaptation throughout Earth's history. Despite extensive research into protein-ligand interactions, the evolution of their binding thermodynamics, particularly regarding enthalpy-entropy trade-offs, remains underexplored. This review compares experimental and computational findings to illustrate how the balance of thermodynamics influences protein structure and function over time. We hypothesize that ancient proteins likely exhibit entropically favored, flexible binding modes, while modern proteins increasingly rely on enthalpically driven specificity. Evolutionary trajectories, including those from ancestral sequence reconstruction studies and modern viral evolution, reveal that thermodynamic trade-offs allow proteins to adapt to diverse functions. Our evolutionary perspective on the existing research demonstrates that binding thermodynamics not only govern ligand affinity and specificity but also fundamentally shape protein evolution and inform potential protein engineering strategies.