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首页> 外文期刊>Biochemistry >Why Does Asn71 Deamidate Faster Than Asn15 in the Enzyme Triosephosphate Isomerase? Answers from Microsecond Molecular Dynamics Simulation and QM/MM Free Energy Calculations
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Why Does Asn71 Deamidate Faster Than Asn15 in the Enzyme Triosephosphate Isomerase? Answers from Microsecond Molecular Dynamics Simulation and QM/MM Free Energy Calculations

机译：为什么ASN71脱胺比酶Triosephysephate异构酶中的ASN15更快？ 从微秒分子动力学模拟和QM / MM自由能量计算的答案

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摘要

Deamidation is the uncatalyzed process by which asparagine or glutamine can be transformed into aspartic acid or glutamic acid, respectively. In its active homodimeric form, mammalian triosephosphate isomerase (TPI) contains two deamidation sites per monomer. Experimental evidence shows that the primary deamidation site (Asn71-Gly72) deamidates faster than the secondary deamidation site (Asn15-Gly16). To evaluate the factors controlling the rates of these two deamidation sites in TPI, we have performed graphics processing unit-enabled microsecond long molecular dynamics simulations of rabbit TPI. The kinetics of asparagine dipeptide and two deamidation sites in mammalian TPI are also investigated using quantum mechanical/molecular mechanical tools with the umbrella sampling technique. Analysis of the simulations has been performed using independent global and local descriptors that can influence the deamidation rates: desolvation effects, backbone acidity, and side chain conformations. Our findings show that all the descriptors add up to favor the primary deamidation site over the secondary one in mammalian TPI: Asn71 deamidates faster because it is more solvent accessible, the adjacent glycine NH backbone acidity is enhanced, and the Asn side chain has a preferential near attack conformation. The crucial impact of the backbone amide acidity of the adjacent glycine on the deamidation rate is shown by kinetic analysis. Our findings also shed light on the effect of high-order structure on deamidation: the deamidation in a small peptide is favored first because of the higher reactivity of the asparagine residue and then because of the stronger stability of the tetrahedral intermediate.
机译：脱酰胺是未催化的工艺，可以分别转化到天冬氨酸或谷氨酸中的天冬酰胺或谷氨酰胺。在其活性同型二聚体形式中，哺乳动物Triosephosphate异构酶（TPI）含有每单体的两个脱胺位点。实验证据表明，初级脱胺位点（ASN71-GLY72）脱次比二次脱染点（ASN15-GLY16）脱染。为了评估控制TPI中这两种脱胺位点的速率的因素，我们已经执行了兔TPI的支持单元的微秒长分子动力学模拟。使用伞形机械/分子机械工具，用伞采样技术研究了天冬酰胺二肽和哺乳动物TPI中的两种脱酰胺位点的动力学。已经使用独立的全局和本地描述符进行了对模拟的分析，这些描述符可以影响脱胺率：脱溶解效果，骨干酸度和侧链构象。我们的研究结果表明，所有的描述符都在哺乳动物TPI中赞成初级脱胺位点：ASN71脱胺更快，因为它更溶剂可接近，因此相邻的甘氨酸NH骨架酸度得到增强，ASN侧链具有优先级近攻击构象。通过动力学分析显示了相邻甘氨酸的骨干酰胺酸度对脱染速率的关键影响。我们的研究结果还阐明了高阶结构对脱染的影响：由于天冬酰胺残留物的反应性更高，因此首先优先于小肽的脱染，然后是由于四面体中间体的稳定性较强。

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  • 来源
    《Biochemistry》 |2015年第6期|共11页
  • 作者

    Ugur Ilke; Marion Antoine; Aviyente Viktorya; Monard Gerald;

  • 作者单位

    Univ Lorraine UMR SRSMC 7565 F-54506 Vandoeuvre Les Nancy France;

    Univ Lorraine UMR SRSMC 7565 F-54506 Vandoeuvre Les Nancy France;

    Bogazici Univ Dept Chem TR-34342 Istanbul Turkey;

    Univ Lorraine UMR SRSMC 7565 F-54506 Vandoeuvre Les Nancy France;

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  • 正文语种 eng
  • 中图分类 生物化学;
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