Atomistic Model for the Polyamide Formation from β-Lactam Catalyzed by Candida antarctica Lipase B

Candida antarctica lipase B (CALB) is an established biocatalyst for a variety of transesterification, amidation, and polymerization reactions. In contrast to polyesters, polyamides are not yet generally accessible via enzymatic polymerization. In this regard, an enzyme-catalyzed ring-opening polymerization of β-lactam (2-azetidinone) using CALB is the first example of an enzymatic polyamide formation yielding unbranched poly(β-alanine), nylon 3. The performance of this polymerization, however, is poor, considering the maximum chain length of 18 monomer units with an average length of 8, and the molecular basis of the reaction so far is not understood. We have employed molecular modeling techniques using docking tools, molecular dynamics, and QM/MM procedures to gain insight into the mechanistic details of the various reaction steps involved. As a result, we propose a catalytic cycle for the oligomerization of β-lactam that rationalizes the activation of the monomer, the chain elongation by additional β-lactam molecules, and the termination of the polymer chain. In addition, the processes leading to a premature chain termination are studied. Particularly, the QM/MMcalculation enables an atomistic description of all eight steps involved in the catalytic cycle, which features an in situ-generated β-alanine as the elongating monomer and which is compatible with the experimental findings.