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Seeking the Source of Catalytic Efficiency of Lindane Dehydrochlorinase, LinA
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2020-11-04 , DOI: 10.1021/acs.jpcb.0c08976 Agata Sowińska 1 , Luis Vasquez 1 , Szymon Żaczek 1 , Rabindra Nath Manna 2 , Iñaki Tuñón 3 , Agnieszka Dybala-Defratyka 1
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2020-11-04 , DOI: 10.1021/acs.jpcb.0c08976 Agata Sowińska 1 , Luis Vasquez 1 , Szymon Żaczek 1 , Rabindra Nath Manna 2 , Iñaki Tuñón 3 , Agnieszka Dybala-Defratyka 1
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Herein we present the results of an in-depth simulation study of LinA and its two variants. In our analysis, we combined the exploration of protein conformational dynamics with and without bound substrates (hexachlorocyclohexane (HCH) isomers) performed using molecular dynamics simulation followed by the extraction of the most frequently visited conformations and their characteristics with a detailed description of the interactions taking place in the active site between the respective HCH molecule and the first shell residues by using symmetry-adapted perturbation theory (SAPT) calculations. A detailed investigation of the conformational space of LinA substates has been accompanied by description of enzymatic catalytic steps carried out using a hybrid quantum mechanics/molecular mechanics (QM/MM) potential along with the computation of the potential of mean force (PMF) to estimate the free energy barriers for the studied transformations: dehydrochlorination of γ-, (−)-α-, and (+)-α-HCH by LinA-type I and -type II variants. The applied combination of computational techniques allowed us not only to characterize two LinA types but also to point to the most important differences between them and link their features to catalytic efficiency each of them possesses toward the respective ligand. More importantly it has been demonstrated that type I protein is more mobile, its active site has a larger volume, and the dehydrochlorination products are stabilized more strongly than in the case of type II enzyme, due to differences in the residues present in the active sites. Additionally, interaction energy calculations revealed very interesting patterns not predicted before but having the potential to be utilized in any attempts of improving LinA catalytic efficiency. On the basis of all these observations, LinA-type I protein seems to be more preorganized for the dehydrochlorination reaction it catalyzes than the type II variant.
中文翻译：
寻找林丹脱氢酶Lina的催化效率来源
本文中，我们介绍了LinA及其两个变体的深入仿真研究结果。在我们的分析中，我们结合了使用分子动力学模拟对有无结合底物（六氯环己烷（HCH）异构体）进行蛋白构象动力学的探索，然后提取了最常访问的构象及其特征，并详细描述了相互作用。通过使用对称适应性扰动理论（SAPT）计算，将其放置在各个HCH分子和第一个壳残基之间的活性位点。对LinA亚型构象空间的详细研究伴随着使用混合量子力学/分子力学（QM / MM）势进行的酶催化步骤的描述以及平均力（PMF）势的计算研究的转化的自由能垒：通过LinA I型和II型变体对γ-，（-）-α-和（+）-α-HCH进行脱氯化氢。计算机技术的应用组合不仅使我们能够表征两种LinA类型，而且还指出了它们之间最重要的差异，并将它们的特征与它们各自对各自的配体所具有的催化效率联系起来。更重要的是，已证明I型蛋白更具流动性，其活性位点体积更大，并且由于活性位点中存在的残基差异，脱氢氯化物的稳定性比II型酶更稳定。另外，相互作用能的计算揭示了非常有趣的模式，以前没有预测过，但是有潜力用于提高LinA催化效率的任何尝试中。根据所有这些观察结果，LinA I型蛋白质似乎比II型变异体更能组织其催化的脱氯化氢反应。
更新日期：2020-11-19
中文翻译：
寻找林丹脱氢酶Lina的催化效率来源
本文中，我们介绍了LinA及其两个变体的深入仿真研究结果。在我们的分析中，我们结合了使用分子动力学模拟对有无结合底物（六氯环己烷（HCH）异构体）进行蛋白构象动力学的探索，然后提取了最常访问的构象及其特征，并详细描述了相互作用。通过使用对称适应性扰动理论（SAPT）计算，将其放置在各个HCH分子和第一个壳残基之间的活性位点。对LinA亚型构象空间的详细研究伴随着使用混合量子力学/分子力学（QM / MM）势进行的酶催化步骤的描述以及平均力（PMF）势的计算研究的转化的自由能垒：通过LinA I型和II型变体对γ-，（-）-α-和（+）-α-HCH进行脱氯化氢。计算机技术的应用组合不仅使我们能够表征两种LinA类型，而且还指出了它们之间最重要的差异，并将它们的特征与它们各自对各自的配体所具有的催化效率联系起来。更重要的是，已证明I型蛋白更具流动性，其活性位点体积更大，并且由于活性位点中存在的残基差异，脱氢氯化物的稳定性比II型酶更稳定。另外，相互作用能的计算揭示了非常有趣的模式，以前没有预测过，但是有潜力用于提高LinA催化效率的任何尝试中。根据所有这些观察结果，LinA I型蛋白质似乎比II型变异体更能组织其催化的脱氯化氢反应。
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