Making sense of chaos: uncovering the mechanisms of conformational entropy

During protein folding, proteins transition from a disordered polymer into a globular structure, markedly decreasing their conformational degrees of freedom and consequently leading to a substantial reduction in entropy. Nonetheless, folded proteins still retain significant entropy as they fluctuate between the conformations that make up their native state. This residual entropy contributes to crucial functions like binding or catalysis. Here, we outline three major ways that protein use conformational entropy to perform their functions; first, pre-paying entropic cost through ordering of the ground state; second, spatially redistributing entropy, where an decrease in entropy in one area is reciprocated by an increase in entropy elsewhere; third, populating catalytically-competent ensembles, where conformational entropy within the enzymatic scaffold aids in lowering transition state barriers. Given the growing evidence of the biological significance of conformational entropy, emerging largely from NMR and simulation studies, solving the current challenge of structurally defining the ensembles encoding conformational entropy will open new paths for control of binding, catalysis, and allostery.