During protein folding, proteins transition from a disordered polymer into a globular structure, markedly decreasing their conformational degrees of freedom, leading to a substantial reduction in entropy. Nonetheless, folded proteins retain substantial entropy as they fluctuate between the conformations that make up their native state. This residual entropy contributes to crucial functions like binding and catalysis, supported by growing evidence primarily from NMR and simulation studies. Here, we propose three major ways that macromolecules use conformational entropy to perform their functions; first, prepaying entropic cost through ordering of the ground state; second, spatially redistributing entropy, in which a decrease in entropy in one area is reciprocated by an increase in entropy elsewhere; third, populating catalytically competent ensembles, in which conformational entropy within the enzymatic scaffold aids in lowering transition state barriers. We also provide our perspective on how solving the current challenge of structurally defining the ensembles encoding conformational entropy will lead to new possibilities for controlling binding, catalysis and allostery.
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