Figure 3.

Diagrammatic illustration of potential catalysis that can be obtained from a greater strengthening of H bonds accompanying charge rearrangements at a nonaqueous enzymatic active site than in water, using the example of the TIM reaction. The pK_a of the substrate carbonyl oxygen increases during the course of reaction, so that ΔpK_a between this oxygen atom and the enzymatic or solution H bond donor (His-E or HOH, respectively) decreases. This leads to an increase in H bond strength. This increase would be greater at the enzymatic active site (ΔΔG^E) than in solution (ΔΔG^soln) because of the greater Brønsted slopes in nonaqueous environments. The amount of catalysis obtained from this strategy, relative to the solution reaction, is ΔΔG^≠ = ΔΔG^E − ΔΔG^soln.