(A, B) Cartoon illustrations of two rigidly linked well-structured domains in an assumed mechanical model. The allosteric site is on the right, above its ligand (black downward arrow), and the functional site is on the left, below its binding partner (black upward arrow). Binding at the allosteric site pivots the rigid linker around a fulcrum; this applies a force to the domain containing the functional site, which binds to its partner. (C) Cartoon illustration of allosteric coupling between a structured domain (left) and a disordered domain (right). The flexibility of the disordered region means that a force is not directly applied to the structured domain when the disordered region binds to its binding partner (black downward arrows). (D) Nevertheless, binding of the disordered region alters the energetics of the system in a way that makes binding at the functional site more favorable. In this illustrative case, we simulate these energetics by placing our mechanical system in a water bath (blue dashed line). By binding to its ligand (bottom right), the disordered domain raises the water level in the bath (blue upward arrow in C), indirectly causing the domain containing the functional site to float closer to its target. In real proteins, the energetic coupling is mediated by the rebalancing of the ensemble of different possible states that occurs when the allosteric site binds to its ligand (see Hilser and Thompson, 2007).