Binding affinity is largely dictated by the surface complementarity and attractive interactions (e.g. hydrogen bonds) between the ligand and the receptor. Like folding, both these features greatly constrain the potential conformations the receptor can adopt, incurring an entropic penalty. The loss of conformational entropy is countered largely by the free energy gained by these interactions. However, if the ground state conformational ensemble is restricted to a similar extent to those adopted in the bound state, the protein pre-pays the entropic penalty. The cost of the entropic penalty can be minimized or even rendered non-existent. This simple concept extends most interestingly to cooperativity in allostery. Consider an allosteric system with two binding sites, each of which must be well-ordered to stably bind a ligand. The first binding event significantly reduces the conformational freedom of side chains across the protein, paying a large entropic penalty . This reduction in conformational heterogeneity can stabilize binding-competent conformations at the second binding site. In this scenario, the first event 'pre-pays' the entropic penalty of the second binding event and reduces the entropic organization penalty for stabilizing the binding-competent conformation. Compared to a scenario where the second binding site remains dynamic, allosteric ordering lowers the energy gap for the second binding event, leading to an observation of 'positive cooperativity'(Figure ).