FIGURE 1. Reaction scheme and catalytic motifs used in design.

a, The Kemp elimination proceeds by means of a single transition state, which can be stabilized by a base deprotonating the carbon and the dispersion of the resulting negative charge; a hydrogen bond donor can also be used to stabilize the partial negative charge on the phenolic oxygen. b, Examples of active site motifs highlighting the two choices for the catalytic base (a carboxylate (left) or a His–Asp dyad (right)) used for deprotonation, and a -stacking aromatic residue for transition state stabilization. For each catalytic base, all combinations of hydrogen bond donor groups (Lys, Arg, Ser, Tyr, His, water or none) and -stacking interactions (Phe, Tyr, Trp) were input as active site motifs into RosettaMatch.