Computational study of a model system of enzyme-mediated [4+2] cycloaddition reaction

PLoS One. 2015 Apr 8;10(4):e0119984. doi: 10.1371/journal.pone.0119984. eCollection 2015.

Abstract

A possible mechanistic pathway related to an enzyme-catalyzed [4+2] cycloaddition reaction 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biocatalysis*
  • Cycloaddition Reaction*
  • Enzymes / metabolism*
  • Hydrogen Bonding
  • Macrolides / chemistry*
  • Models, Chemical*
  • Models, Molecular
  • Molecular Conformation
  • Thermodynamics

Substances

  • Enzymes
  • Macrolides
  • spinosyn A

Grants and funding

EGG acknowledges support from Russian Foundation for Basic Research (grant: 14-03-31752), VPA acknowledges support from Russian Science Foundation (RSF grant 14-50-00126). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.