Comparative Theoretical Study of the Ring-Opening Polymerization of Caprolactam vs Caprolactone Using QM/MM Methods

Candida antarctica lipase
B (CALB) efficiently
catalyzes the ring-opening polymerization of lactones to high molecular
weight products in good yield. In contrast, an efficient enzymatic
synthesis of polyamides has so far not been described in the literature.
This obvious difference in enzyme catalysis is the subject of our
comparative study of the initial steps of a CALB catalyzed ring-opening
polymerization of ε-caprolactone and ε-caprolactam. We
have applied docking tools to generate the reactant state complex
and performed quantum mechanical/molecular mechanical (QM/MM) calculations
at the density functional theory (DFT) PBE0 level of theory to simulate
the acylation of Ser105 by the lactone and the lactam, respectively,
via the corresponding first tetrahedral intermediates. We could identify
a decisive difference in the accessibility of the two substrates in
the ring-opening to the respective acyl enzyme complex as the attack
of ε-caprolactam is hindered because of an energetically disfavored
proton transfer during this part of the catalytic reaction while ε-caprolactone
is perfectly processed along the widely accepted pathway using the
catalytic triade of Ser105, His224, and Asp187. Since the generation
of an acylated Ser105 species is the crucial step of the polymerization
procedure, our results give an explanation for the unsatisfactory
enzymatic polyamide formation and opens up new possibilities for targeted
rational catalyst redesign in hope of an experimentally useful CALB
catalyzed polyamide synthesis