Proton Transfer and SN2 Reactions as Steps of Fast Selenol and Thiol Oxidation in Proteins: A Model Molecular Study Based on GPx,ChemPlusChem

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Proton Transfer and SN2 Reactions as Steps of Fast Selenol and Thiol Oxidation in Proteins: A Model Molecular Study Based on GPx
ChemPlusChem ( IF 3.0 ) Pub Date : 2020-11-09 , DOI: 10.1002/cplu.202000660
Marco Dalla Tiezza ₁ , F Matthias Bickelhaupt _{2,

3} , Leopold Flohé _{4,

5} , Laura Orian ₁

Affiliation

The so‐called peroxidatic cysteines and selenocysteines in proteins reduce hydroperoxides through a dual attack to the peroxide bond in a two‐step mechanism. First, a proton dislocation from the thiol/selenol to a close residue of the enzymatic pocket occurs. Then, a nucleophilic attack of the anionic cysteine/selenocysteine to one O atom takes place, while the proton is shuttled back to the second O atom, promoting the formation of a water molecule. In this computational study, we use a molecular model of GPx to demonstrate that the enzymatic environment significantly lowers the barrier of the latter S_N2 step. Particularly, in our Se‐based model the energy barriers for the two steps are 29.82 and 2.83 kcal mol⁻¹, both higher than the corresponding barriers computed in the enzymatic cluster, i. e., 21.60 and null, respectively. Our results, obtained at SMD‐B3LYP‐D3(BJ)/6‐311+G(d,p), cc‐pVTZ//B3LYP‐D3(BJ)/6‐311G(d,p), cc‐pVTZ level of theory, show that the mechanistic details can be well reproduced using an oversimplified model, but the energetics is definitively more favorable in the GPx active site. In addition, we pinpoint the role of the chalcogen in the peroxide reduction process, rooting the advantages of the presence of selenium in its acidic and nucleophilic properties.

中文翻译：

作为蛋白质中快速硒醇和硫醇氧化步骤的质子转移和 SN2 反应：基于 GPx 的模型分子研究

蛋白质中所谓的过氧化半胱氨酸和硒代半胱氨酸通过在两步机制中对过氧化物键的双重攻击来减少氢过氧化物。首先，发生从硫醇/硒醇到酶袋的紧密残基的质子位错。然后，阴离子半胱氨酸/硒代半胱氨酸对一个 O 原子进行亲核攻击，同时质子穿梭回第二个 O 原子，促进水分子的形成。在这项计算研究中，我们使用 GPx 的分子模型来证明酶促环境显着降低了后一个 S _N 2 步骤的障碍。特别是，在我们基于硒的模型中，两个步骤的能垒分别为 29.82 和 2.83 kcal mol ^-1，均高于酶簇中计算的相应障碍，即。例如，分别为 21.60 和 null。我们的结果，在 SMD-B3LYP-D3(BJ)/6-311+G(d,p), cc-pVTZ//B3LYP-D3(BJ)/6-311G(d,p), cc-pVTZ 水平上获得理论上，表明使用过度简化的模型可以很好地再现机械细节，但能量学在 GPx 活性位点中肯定更有利。此外，我们指出了硫属元素在过氧化物还原过程中的作用，将硒的存在优势在于其酸性和亲核特性。

更新日期：2020-11-09

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