Rapid computational evaluation of small-molecule hydrolase mimics for preorganized H-bond networks

Spirocyclic oligomers formed by coupling chiral cyclic building blocks carrying the catalytic machinery of hydrolases (spiroligozymes) catalyze the transesterification of vinyl trifluoromethylacetate with methanol but suffer from the lack of enzyme-like preorganization of their catalytic functionalities in a well-defined geometry via H-bond networks. The computational protocol presented herein combines different levels of theories to rapidly explore structural modifications for an improved structural preorganization. Calculations predict that a modification as simple as replacing the five-membered building block holding the alcohol moiety with a six-membered analog in spiroligozymes significantly increases the occupancy of the H-bond between the benzyl alcohol-pyridine nucleophilic dyad that mimics the Ser-His-Asp/Glu triad of hydrolases. The computed energy profile is indicative of faster acylation of this derivative compared to the parent spiroligozyme and highlights the importance of inclusion of an oxyanion hole motif for efficient catalysis.