Computational Insights into an Enzyme-Catalyzed [4+2] Cycloaddition.

ABSTRACT: The enzyme SpnF, involved in the biosynthesis of spinosyn A, catalyzes a formal [4+2] cycloaddition of a 22-membered macrolactone, which may proceed as a concerted [4+2] Diels-Alder reaction or a stepwise [6+4] cycloaddition followed by a Cope rearrangement. Quantum mechanics/molecular mechanics (QM/MM) calculations combined with free energy simulations show that the Diels-Alder pathway is favored in the enzyme environment. OM2/CHARMM free energy simulations for the SpnF-catalyzed reaction predict a free energy barrier of 22 kcal/mol for the concerted Diels-Alder process and provide no evidence of a competitive stepwise pathway. Compared with the gas phase, the enzyme lowers the Diels-Alder barrier significantly, consistent with experimental observations. Inspection of the optimized geomet

SUBMITTER: Zheng Y 

PROVIDER: S-EPMC5735378 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature