Predicting Activation Barriers With Ring and Bond Critical Points in the Kemp Elimination Reaction

The Kemp elimination reaction can be catalyzed by computationally designed enzymes. After undergoing directed evolution, changes to the positioning of active site residues in Kemp eliminases can alter electric fields (EFs) and improve catalytic efficiency. However, optimizing EFs during the enzyme design process remains a challenge. Here we investigate how implicit solvation and external EFs reposition bond and ring critical points (CPs) in the reactant state of a truncated Kemp eliminase system using density functional theory and the quantum theory of atoms in molecules. We find that a linear correlation exists between the bond-ring CP distances integral to the Kemp elimination ring-opening reaction and activation barriers. The N─O stretching mode of the benzisoxazole ring that coincides with the reaction coordinate is also found to move ring CPs to varying degrees for each EF strength tested. EFs that move the ring CPs the largest magnitude and in the proper orientation toward the N─O bond CP correlate with the smallest activation barriers. Since reactant state QTAIM calculations are significantly less expensive than directly calculating activation barriers, this may provide an avenue for screening computationally designed enzymes that catalyze ring-opening reactions.