These examples show how both negative and positive cooperativity can result from changes in the conformational distributions that accompany initial binding events. These variations in conformational distributions arise not only from significant shifts in their dominant conformation (conformational change) but also, crucially, from fluctuations. Pre-paying (or, in the case of negative cooperativity, exacerbating) entropic penalties is a key way proteins allosterically control function. A greater structural understanding of the entropic and reorganization penalties accompanying these binding events may be especially therapeutically relevant to double-drugging strategies .