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Origin of Chemoselectivity of Halohydrin Dehalogenase-Catalyzed Epoxide Ring-Opening Reactions
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-05-29 , DOI: 10.1021/acs.jcim.4c00640 Qian-Qian Wang 1 , Jinshuai Song 1 , Donghui Wei 1
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-05-29 , DOI: 10.1021/acs.jcim.4c00640 Qian-Qian Wang 1 , Jinshuai Song 1 , Donghui Wei 1
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By performing molecular dynamics (MD), quantum mechanical/molecular mechanical (QM/MM) calculations, and QM cluster calculations, the origin of chemoselectivity of halohydrin dehalogenase (HHDH)-catalyzed ring-opening reactions of epoxide with the nucleophilic reagent NO2− has been explored. Four possible chemoselective pathways were considered, and the computed results indicate that the pathway associated with the nucleophilic attack on the Cα position of epoxide by NO2− is most energetically favorable and has an energy barrier of 12.9 kcal/mol, which is close to 14.1 kcal/mol derived from experimental kinetic data. A hydrogen bonding network formed by residues Ser140, Tyr153, and Arg157 can strengthen the electrophilicity of the active site of the epoxide substrate to affect chemoselectivity. To predict the energy barrier trends of the chemoselective transition states, multiple analyses including distortion analysis and electrophilic Parr function (Pk+) analysis were carried out with or without an enzyme environment. The obtained insights should be valuable for the rational design of enzyme-catalyzed and biomimetic organocatalytic epoxide ring-opening reactions with special chemoselectivity.
中文翻译：
卤代醇脱卤酶催化环氧化物开环反应化学选择性的起源
通过进行分子动力学（MD）、量子力学/分子力学（QM/MM）计算和QM簇计算，卤代醇脱卤酶（HHDH）催化环氧化物与亲核试剂NO 2 −的开环反应的化学选择性的起源已被探索。考虑了四种可能的化学选择性途径，计算结果表明，与NO 2 -对环氧化物Cα位置的亲核攻击相关的途径在能量上最有利，并且具有12.9 kcal/mol的能量势垒，接近14.1 kcal/mol。 kcal/mol 来自实验动力学数据。 Ser140、Tyr153和Arg157残基形成的氢键网络可以增强环氧化物底物活性位点的亲电性，从而影响化学选择性。为了预测化学选择性过渡态的能垒趋势，在有或没有酶环境的情况下进行了多种分析，包括畸变分析和亲电子帕尔函数（ P k + ）分析。所获得的见解对于合理设计具有特殊化学选择性的酶催化和仿生有机催化环氧化物开环反应具有重要价值。
更新日期：2024-05-29
中文翻译：
卤代醇脱卤酶催化环氧化物开环反应化学选择性的起源
通过进行分子动力学（MD）、量子力学/分子力学（QM/MM）计算和QM簇计算，卤代醇脱卤酶（HHDH）催化环氧化物与亲核试剂NO 2 −的开环反应的化学选择性的起源已被探索。考虑了四种可能的化学选择性途径，计算结果表明，与NO 2 -对环氧化物Cα位置的亲核攻击相关的途径在能量上最有利，并且具有12.9 kcal/mol的能量势垒，接近14.1 kcal/mol。 kcal/mol 来自实验动力学数据。 Ser140、Tyr153和Arg157残基形成的氢键网络可以增强环氧化物底物活性位点的亲电性，从而影响化学选择性。为了预测化学选择性过渡态的能垒趋势，在有或没有酶环境的情况下进行了多种分析，包括畸变分析和亲电子帕尔函数（ P k + ）分析。所获得的见解对于合理设计具有特殊化学选择性的酶催化和仿生有机催化环氧化物开环反应具有重要价值。
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