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Reid and Sigman1 report a computational model that predicts the outcome of reactions when a wide range of nucleophilic molecules react with imines in the presence of a catalyst, accounting for factors such as molecular structure and solvent.

The Me-His residue in the modified enzymes acts as a nucleophilic catalyst that is broadly analogous to the nucleophilic residues found in serine hydrolase and cysteine hydrolase enzymes.

After the first tetradepsipeptide has been loaded onto the nucleophilic residue in the thioesterase domain, the second tetradepsipeptide arrives at the thioesterase active site, attached to the carrier domain.

For example, Liljas . argue that His must be protonated and donating a hydrogen bond to the nucleophilic water, in part because the water hydrogens are interacting with the carbonyl oxygen of Thr62 and the γ-phosphate of GTP.

Arginine fingers can also interact with a nonbridging oxygen of the γ-phosphate, but His would have to change conformation to accomplish this, which would likely disrupt its interaction with the nucleophilic water and weaken the interaction between His and the phosphate of A2662 of the sarcin-ricin loop.