There is a growing appreciation in protein biochemistry that protein structures should not be regarded as static snapshots of atomic coordinates but rather as ensembles of conformations. Beyond thermal fluctuations, conformational changes are commonly observed in many biochemical processes such as substrate binding or pH changes. Simply speaking, many proteins require more than one conformational state to perform their functions. Many of these "alternative" conformations are theraputically important, as rationally designed drugs often need to target one specific state of a protein. However, structures of these metastable states are often difficult to resolve experimentally. Fast protein dynamics can exceed the time resolution of structural determination methods; additionally, it is not possible to resolve a holo-like structure with an empty substrate binding site. As a result, experimentally determined structures often represent an ensemble average of all possible conformations, with a strong emphasis on the lowest free-energy "native" state.