Computational Study of a Model System of Enzyme-Mediated [4+2] Cycloaddition Reaction

Abstract

A possible mechanistic pathway related to an enzyme-catalyzed [4+2] cycloaddition reac-tion was studied by theoretical calculations at density functional (B3LYP, O3LYP, M062X) and semiempirical levels (PM6-DH2, PM6) performed on a model system. The calculations were carried out for the key [4+2] cycloaddition step considering enzyme-catalyzed biosynthesis of Spinosyn A in a model reaction, where a reliable example of a biological Diels-Alder reaction was reported experimentally. In the present study it was demonstrated that the [4+2] cycloaddition reaction may benefit from moving along the energetically balanced reaction coordinate, which enabled the catalytic rate enhancement of the [4+2] cycloaddition pathway involving a single transition state. Modeling of such a system with coordination of three amino acids indicated a reliable decrease of activation energy by ~18.0 kcal/mol as compared to a non-catalytic transformation.

Benchmarking of density functionals for the kinetics and thermodynamics of the hydrolysis of glycosidic bonds catalyzed by glycosidases

“…Semiempirical MO methods sometimes are adopted to optimize geometries of large systems . As such, we also tested the performance of a few semiempirical MO methods in our model system, namely AM1, PM3, PM6, and PGGD.…”

“…Semiempirical MO methods sometimes are adopted to optimize geometries of large systems. [42,118,119] As such, we also tested the performance of a few semiempirical MO methods in our model system, namely AM1, PM3, PM6, and PGGD. The structures optimized with the semiempirical MO methods show significant differences in relation to the structures optimized with MP2/aug-cc-pVTZ or with the DFs.…”

Natural [4 + 2]-Cyclases

“…145 A later study by Gordeev and Ananikov helped to extend these results by including H-bonding interactions between modeled amino acids and the C9 and C17 hydroxyls as well as the C15 carbonyl. 146 Their results also implicated a single transition state with respect to the [4 + 2]-cycloaddition while at the same time highlighting how both H-bonding and conformational preorganization of the substrate in the active site could account for the observed rate enhancement by SpnF. Together, these results implicated a highly asynchronous Diels-Alder reaction for the cyclization and provided a rationale for SpnF catalysis consistent with hypotheses based on crystal structures of other [4 + 2]-carbocyclases.…”

Biocatalytic Strategies towards [4+2] Cycloadditions

“…There have been extensive computational investigations into the SpnF‐catalysed reaction utilising multiple approaches (Scheme B) . These simulations are based on the SpnF crystal structure and computational docking and show multiple mechanisms in the gas‐phase leading to the [4+2] product 23 .…”

“…[60,64] There have been extensive computational investigations into the SpnF-catalysed reaction utilisingm ultiple approaches (Scheme 4B). [61][62][63][65][66][67][68] These simulations are based on the SpnF crystal structurea nd computational docking [64] and show multiple mechanisms in the gas-phase leading to the [4+ +2] product 23.A longside the direct route via ac oncerted [4+ +2] transition state, Patel et al [67] proposed an alternative route via [6+ +4] intermediate 24 whichundergoes aCope rearrangement to revealt he [4+ +2] product 23.F urthermore, they propose that the initial transition state is ambimodal and able to lead to either [4+ +2] or [6+ +4] adducts.…”