Rational Redesign of Enzyme via the Combination of Quantum Mechanics/Molecular Mechanics, Molecular Dynamics, and Structural Biology Study

Hong Yan Lin, Xi Chen, Jin Dong, Jing Fang Yang, Han Xiao, Ying Ye, Lin Hui Li, Chang Guo Zhan, Wen Chao Yang, Guang Fu Yang

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Increasing demands for efficient and versatile chemical reactions have prompted innovations in enzyme engineering. A major challenge in engineering α-ketoglutarate-dependent oxygenases is to develop a rational strategy which can be widely used for directly evolving the desired mutant to generate new products. Herein, we report a strategy for rational redesign of a model enzyme, 4-hydroxyphenylpyruvate dioxygenase (HPPD), based on quantum mechanics/molecular mechanics (QM/MM) calculation and molecular dynamic simulations. This strategy enriched our understanding of the HPPD catalytic reaction pathway and led to the discovery of a series of HPPD mutants producing hydroxyphenylacetate (HPA) as the alternative product other than the native product homogentisate. The predicted HPPD-Fe(IV)═O-HPA intermediate was further confirmed by the crystal structure of Arabidopsis thaliana HPPD/S267W complexed with HPA. These findings not only provide a good understanding of the structure-function relationship of HPPD but also demonstrate a generally applicable platform for the development of biocatalysts.

Original languageEnglish
Pages (from-to)15674-15687
Number of pages14
JournalJournal of the American Chemical Society
Volume143
Issue number38
DOIs
StatePublished - Sep 29 2021

Bibliographical note

Publisher Copyright:
© 2021 American Chemical Society.

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry

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