Influence of water and enzyme SpnF on the dynamics and energetics of the ambimodal [6+4]/[4+2] cycloaddition

Zhongyue Yang, Song Yang, Peiyuan Yu, Yanwei Li, Charles Doubleday, Jiyong Park, Ashay Patel, Byung sun Jeon, William K. Russell, Hung wen Liu, David H. Russell, Kendall N. Houk

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


SpnF is the first monofunctional Diels–Alder/[6+4]-ase that catalyzes a reaction leading to both Diels–Alder and [6+4] adducts through a single transition state. The environment-perturbed transition-state sampling method has been developed to calculate free energies, kinetic isotope effects, and quasi-classical reaction trajectories of enzyme-catalyzed reactions and the uncatalyzed reaction in water. Energetics calculated in this way reproduce the experiment and show that the normal Diels–Alder transition state is stabilized by H bonds with water molecules, while the ambimodal transition state is favored in the enzyme SpnF by both intramolecular hydrogen bonding and hydrophobic binding. Molecular dynamics simulations show that trajectories passing through the ambimodal transition state bifurcate to the [6+4] adduct and the Diels–Alder adduct with a ratio of 1:1 in the gas phase, 1:1.6 in water, and 1:11 in the enzyme. This example shows how an enzyme acts on a vibrational time scale to steer post-transition state trajectories toward the Diels–Alder adduct.

Original languageEnglish (US)
Pages (from-to)E848-E855
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
StatePublished - Jan 30 2018
Externally publishedYes


  • Environment-perturbed
  • Potential energy surface bifurcation
  • SpnF enzyme
  • Time-resolved mechanism
  • Transition-state sampling

ASJC Scopus subject areas

  • General


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