Rational Design of P450 aMOx for Improving Anti-Markovnikov Selectivity Based on the “Butterfly” Model

Yue Pan; Jinxiao Bao; Xingyi Zhang; Hui Ni; Yue Zhao; Fengdong Zhi; Bohuan Fang; Xiao He; John Z.H. Zhang; Lujia Zhang

doi:10.3389/fmolb.2022.888721

Rational Design of P450 aMOx for Improving Anti-Markovnikov Selectivity Based on the “Butterfly” Model

Yue Pan, Jinxiao Bao, Xingyi Zhang, Hui Ni, Yue Zhao, Fengdong Zhi, Bohuan Fang, Xiao He, John Z.H. Zhang, Lujia Zhang

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Aromatic aldehydes are important industrial raw materials mainly synthesized by anti-Markovnikov (AM) oxidation of corresponding aromatic olefins. The AM product selectivity remains a big challenge. P450 aMOx is the first reported enzyme that could catalyze AM oxidation of aromatic olefins. Here, we reported a rational design strategy based on the “butterfly” model of the active site of P450 aMOx. Constrained molecular dynamic simulations and a binding energy analysis of key residuals combined with an experimental alanine scan were applied. As a result, the mutant A275G showed high AM selectivity of >99%. The results also proved that the “butterfly” model is an effective design strategy for enzymes.

Original language	English (US)
Article number	888721
Journal	Frontiers in Molecular Biosciences
Volume	9
DOIs	https://doi.org/10.3389/fmolb.2022.888721
State	Published - May 23 2022

Keywords

anti-Markovnikov (AM) oxidation
experimental alanine scan
molecular dynamic simulations
product selectivity
rational design
“butterfly” model

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Biochemistry, Genetics and Molecular Biology (miscellaneous)

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10.3389/fmolb.2022.888721

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title = "Rational Design of P450 aMOx for Improving Anti-Markovnikov Selectivity Based on the “Butterfly” Model",

abstract = "Aromatic aldehydes are important industrial raw materials mainly synthesized by anti-Markovnikov (AM) oxidation of corresponding aromatic olefins. The AM product selectivity remains a big challenge. P450 aMOx is the first reported enzyme that could catalyze AM oxidation of aromatic olefins. Here, we reported a rational design strategy based on the “butterfly” model of the active site of P450 aMOx. Constrained molecular dynamic simulations and a binding energy analysis of key residuals combined with an experimental alanine scan were applied. As a result, the mutant A275G showed high AM selectivity of >99%. The results also proved that the “butterfly” model is an effective design strategy for enzymes.",

keywords = "anti-Markovnikov (AM) oxidation, experimental alanine scan, molecular dynamic simulations, product selectivity, rational design, “butterfly” model",

author = "Yue Pan and Jinxiao Bao and Xingyi Zhang and Hui Ni and Yue Zhao and Fengdong Zhi and Bohuan Fang and Xiao He and Zhang, {John Z.H.} and Lujia Zhang",

note = "Funding Information: YP: performed the experiments, data processing and analysis, and wrote the manuscript. JB: performed molecular dynamics simulations, data processing and analysis, and wrote the computation part of the manuscript. XZ, YZ, and FZ: performed part of the experiments. BF and XH: reviewed the manuscript. LZ and JZ: gave the support of funding and supervised the project, conceived and designed the study, and edited the manuscript critically. All authors have given approval to the final version of the manuscript. Publisher Copyright: Copyright {\textcopyright} 2022 Pan, Bao, Zhang, Ni, Zhao, Zhi, Fang, He, Zhang and Zhang.",

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doi = "10.3389/fmolb.2022.888721",

language = "English (US)",

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T1 - Rational Design of P450 aMOx for Improving Anti-Markovnikov Selectivity Based on the “Butterfly” Model

AU - Pan, Yue

AU - Bao, Jinxiao

AU - Zhang, Xingyi

AU - Ni, Hui

AU - Zhao, Yue

AU - Zhi, Fengdong

AU - Fang, Bohuan

AU - He, Xiao

AU - Zhang, John Z.H.

AU - Zhang, Lujia

N1 - Funding Information: YP: performed the experiments, data processing and analysis, and wrote the manuscript. JB: performed molecular dynamics simulations, data processing and analysis, and wrote the computation part of the manuscript. XZ, YZ, and FZ: performed part of the experiments. BF and XH: reviewed the manuscript. LZ and JZ: gave the support of funding and supervised the project, conceived and designed the study, and edited the manuscript critically. All authors have given approval to the final version of the manuscript. Publisher Copyright: Copyright © 2022 Pan, Bao, Zhang, Ni, Zhao, Zhi, Fang, He, Zhang and Zhang.

PY - 2022/5/23

Y1 - 2022/5/23

N2 - Aromatic aldehydes are important industrial raw materials mainly synthesized by anti-Markovnikov (AM) oxidation of corresponding aromatic olefins. The AM product selectivity remains a big challenge. P450 aMOx is the first reported enzyme that could catalyze AM oxidation of aromatic olefins. Here, we reported a rational design strategy based on the “butterfly” model of the active site of P450 aMOx. Constrained molecular dynamic simulations and a binding energy analysis of key residuals combined with an experimental alanine scan were applied. As a result, the mutant A275G showed high AM selectivity of >99%. The results also proved that the “butterfly” model is an effective design strategy for enzymes.

AB - Aromatic aldehydes are important industrial raw materials mainly synthesized by anti-Markovnikov (AM) oxidation of corresponding aromatic olefins. The AM product selectivity remains a big challenge. P450 aMOx is the first reported enzyme that could catalyze AM oxidation of aromatic olefins. Here, we reported a rational design strategy based on the “butterfly” model of the active site of P450 aMOx. Constrained molecular dynamic simulations and a binding energy analysis of key residuals combined with an experimental alanine scan were applied. As a result, the mutant A275G showed high AM selectivity of >99%. The results also proved that the “butterfly” model is an effective design strategy for enzymes.

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Rational Design of P450 aMOx for Improving Anti-Markovnikov Selectivity Based on the “Butterfly” Model

Abstract

Keywords

ASJC Scopus subject areas

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