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首页> 外文期刊>Chemistry: A European journal >Theoretical Aspects of Hydrolysis of Peptide Bonds by Zinc Metalloenzymes
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Theoretical Aspects of Hydrolysis of Peptide Bonds by Zinc Metalloenzymes

机译：锌金属酶水解肽键的理论方面

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Activation and reaction energies for four model systems capturing the essential physicochemical features of the hydrolysis of the peptide bond have been calculated at various level of theory, including the presumably accurate CCSD(T) calculations. The models studied covered a part of the spectrum encountered in biological systems: the hydrolysis in the absence of metal ions (represented by formamide and Ala-Ala) and the hydrolysis in the presenceof one and two zinc(II) ions, mimicking the active sites of mono-and dizinc metallopeptidases, respectively (by using thermolysin and glutamate carboxypeptidase II as the model catalytic systems and formamide as the model substrate). The results obtained using CCSD(T)/def2-TZVP and CCSD(T)/aug-cc-pVTZ calculations were used as the benchmark values to which the set of cheaper methods, such as (RI-)DFT, (RI-)MP2, and SCS-MP2, were referenced. It was shown that deviations of 3-5 kcalmol~(-1) (translating to 2-3 orders in reaction constants) with respect to the reference CCSD(T) barriers are frequently encountered for many correlated methods and most of studied DFT functionals. It has been concluded that from the set of wavefunction methods, both MP2 and SCSMP2 methods can be recommended for smaller models (measured by the mean absolute deviation of the activation barriers over the four systems studied), whereas among the popular DFT functionals, B3LYP and especially M06-2X are likely to be reasonable choices for calculating the activation barriers of zinc metallopeptidases. Finally, with the model of glutamate carboxypeptidase II, issues related to the convergence of the calculated barriers with the size of the model system used as the representative of the enzyme active site were addressed. The intricacies related to system truncation are demonstrated, and suggest that the correlated wave-function methods may suffer from problems, such as intramolecular BSSE, which make their usage for the larger system questionable. Altogether, the presented data should contribute to efforts to understand enzymatic catalysis more deeply and to gain control of the accuracy and deficiencies of the available theoretical methods and computational approaches.
机译：四个模型系统的活化和反应能已在各种理论水平上得到了计算，这些系统捕获了肽键水解的基本物理化学特征，包括可能精确的CCSD（T）计算。研究的模型涵盖了生物系统中遇到的部分光谱：在不存在金属离子的情况下进行水解（以甲酰胺和Ala-Ala表示），在存在一个和两个锌（II）离子的情况下（类似于活性位点）进行水解（分别通过使用嗜热菌蛋白酶和谷氨酸羧肽酶II作为模型催化体系，并使用甲酰胺作为模型底物）制备单和二锌金属肽酶。使用CCSD（T）/ def2-TZVP和CCSD（T）/ aug-cc-pVTZ计算获得的结果用作基准值，一组较便宜的方法（如（RI-）DFT，（RI-）引用了MP2和SCS-MP2。结果表明，在许多相关方法和大多数研究的DFT功能中，相对于参考CCSD（T）势垒的偏差通常为3-5 kcalmol〜（-1）（相当于反应常数的2-3个阶）。已经得出结论，从波函数方法的集合中，MP2和SCSMP2方法都可以推荐用于较小的模型（通过研究的四个系统上的激活壁垒的平均绝对偏差来衡量），而在流行的DFT函数中，B3LYP和特别是M06-2X可能是计算锌金属肽酶活性屏障的合理选择。最后，利用谷氨酸羧肽酶II模型，解决了与作为酶活性位点代表的模型系统的大小所计算的屏障的收敛性有关的问题。证明了与系统截断有关的复杂性，并表明相关的波函数方法可能会遇到诸如分子内BSSE之类的问题，这些问题使它们在较大系统中的使用成为问题。总之，所提供的数据应有助于更深入地理解酶催化作用，并获得对可用理论方法和计算方法的准确性和不足的控制。

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