Enzymes catalyze chemical reactions through a high-energy transition state, where active site residues are precisely arranged to orient specific chemical groups responsible for catalysis. It follows that the positioning requirements will lead to an extreme reduction of conformational entropy for active site residues. How can this penalty be offset? One solution is by having these residues preorganized in the apo or substrate-bound states. Another is the Circe effect, where the substrate binds in such a constrained, almost unique conformation, that is entropically disfavored . A third potential strategy is for the enzyme to allow a much broader set of transition states, reducing the entropic penalty required in the binding site . Finally, it is also possible to extend the concept of spatial redistribution for equilibrium ligand binding to catalysis.The capacity of residues in the rest of the enzyme ("the scaffold") to adopt many states that are compatible with the positioning required of catalytic residues throughout the catalytic cycle , can contribute favorably to reducing the entropic penalty of active site positioning. In the extreme case, if the scaffold conformational entropy is higher in the transition state than in the ground state, it can reduce the height of the barrier and entropically favor catalysis. This concept extends beyond the chemical step, which in most cases has a narrow transition state ensemble, to other steps of the catalytic cycle, each of which can be rate-limiting (e.g. substrate binding, product release, conformational change, etc). We call the ensemble of states compatible with the rate-limiting step of catalysis the catalytically-competent ensemble (Figure ).