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Abstract
Protein structures are inherently dynamic and can adopt a wide range of conformations. The ensemble of structural substates that a given protein can explore embodies a conformational landscape, which is essential for various functions (e.g.; binding interactions, catalysis, and regulation). How evolution shapes this conformational landscape to tune specific functions is perplexing. One of the main constraints in the evolution of proteins is the stability of the native folded structure. However, some proteins function in the absence of a stable fold and the persistence (>44%) of intrinsically disordered segments in the human proteome is striking. The bulk of these intrinsically disordered segments have no known function and have been historically regarded as non-functional. Our work shows that the entropic force generated by the intrinsically disordered C-terminus (ID-tail) in human UDP--D-glucose-6-dehydrogenase (hUGDH) biases the conformational landscape to favor a specific substate with higher affinity for an allosteric inhibitor. The function of the ID-tail is independent of both its sequence and chemical composition. Instead, the ID-tail tunes the affinity for the allosteric inhibitor in a length-dependent fashion. This result is consistent with the folded structure incurring an entropic cost by constraining the ID-tail. Our results show that this entropic force generated by the ID-tail alters the dynamics and structure of hUGDH, which favors a substate with higher affinity for the allosteric inhibitor. This entropicforce mechanism alters the conformational landscape of the protein to tune a specific function and has no specific sequence or structural constraints. Thus, our model highlights the utility of intrinsically disordered segments in protein evolution, which may explain the frequency of intrinsic disorder in the proteome.