Proteins differ from small molecule pharmaceuticals not just in their chemical complexity, but in the breadth of their conformational repertoire. In fact, in recent years it has become clear that the static representation afforded by the high-resolution structure is generally insufficient to explain the impact of mutations or changes in solution conditions on the activity or the physico-chemical properties of proteins. Here, we describe how isothermal titration calorimetry (ITC) can be used to in conjunction with other techniques to characterize conformational fluctuations proteins, and that this charcterization can lead to a predictive model of physico-chemical behavior.