Figure 1.

Schematic illustration of the relationship between ligand binding, conformational dynamics, and protein evolution.^7,8 The major conformation adopted by the enzyme is responsible for its native activity, however the existence of minor conformations (that may or may not also be able to interconvert directly) can give rise to promiscuous activities for non-natural substrates. Mutations accumulated over the course of evolutionary trajectories (through either natural or directed evolution) with the appropriate selective pressure(s) can ultimately lead to population shifts, with these minor conformations now becoming the major conformers and the promiscuous activity becoming the new “native” activity. For further discussion, see e.g. refs (7, 8, and 31).