Esterases are enzymes that catalyze the hydrolysis of carboxyl esters. In esterases, the core of the catalytic machinery is the nucleophilic triad composed of Ser-His-Glu amino acids in their active sites. New transesterification catalysts were developed, called “spiroligozymes”, by placing the catalytic machinery of esterase enzymes onto modular spiro-fused bispeptides with the help of quantum mechanical transition state calculations using the “inside-out” approach. In the spiroligozymes the Ser-His-Glu nucleophilic triad was represented by an alcohol-pyridine dyad.The best spiroligozyme increased the rate of the transesterification reaction between vinyl trifluoroacetate and methanol by 2200-fold for acylation step and by 130-fold for the deacylation step. However, the quantum mechanical calculations demonstrated a close relationship between the alignment of alcohol-pyridyl dyad and the activity of the spiroligozymes and showed that the active conformation is 2-3 kcal/mol higher in energy than the most stable conformation. Molecular dynamics simulations revealed that, in contrast to the observed behavior in naturally evolved enzymes, the catalytic groups in spiroligozymes sample numerous alternative conformations beside the active one and the H-bond between the alcohol-pyridyl dyad is not maintained. These computational results suggest that the activities of spiroligozymes can be significantly improved by providing a high-level pre-organization of the catalytic functional groups. In this study, various structural modifications for the previously developed spiroligozymes will be evaluated using quantum mechanical calculations and molecular dynamics simulations in terms of preorganization of the catalytic dyad as mimics of highly conserved hydrogen bond network in enzyme active sites.

Computational design of organocatalysts with preorganized catalytic machinery

256th National Meeting (2018)

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