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Rational Redesign of Enzyme via the Combination of Quantum Mechanics/Molecular Mechanics, Molecular Dynamics, and Structural Biology Study
Journal of the American Chemical Society ( IF 15.0 ) Pub Date : 2021-09-20 , DOI: 10.1021/jacs.1c06227
Hong-Yan Lin 1 , Xi Chen 2 , Jin Dong 1 , Jing-Fang Yang 1 , Han Xiao 1 , Ying Ye 1 , Lin-Hui Li 2 , Chang-Guo Zhan 3 , Wen-Chao Yang 1 , Guang-Fu Yang 1
Affiliation  

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.

中文翻译:

通过结合量子力学/分子力学、分子动力学和结构生物学研究对酶进行合理的重新设计

对高效和多功能化学反应的需求不断增加,推动了酶工程的创新。工程 α-酮戊二酸依赖性加氧酶的一个主要挑战是开发一种合理的策略,该策略可广泛用于直接进化所需的突变体以产生新产品。在此,我们报告了一种基于量子力学/分子力学 (QM/MM) 计算和分子动力学模拟的模型酶 4-羟基苯丙酮酸双加氧酶 (HPPD) 的合理重新设计策略。这一策略丰富了我们对 HPPD 催化反应途径的理解,并导致发现了一系列产生羟基苯乙酸 (HPA) 作为替代产品而非天然产物匀浆的 HPPD 突变体。与 HPA 复合的拟南芥HPPD/S267W。这些发现不仅为HPPD的结构-功能关系提供了一个很好的理解,而且为生物催化剂的开发提供了一个普遍适用的平台。
更新日期:2021-09-29
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