Department de Química Física i Inorgànica, Universitat Rovira i Virgili (URV), Marcel·lí Domingo 1, 43007 Tarragona, Spain.
Inorg Chem. 2021 Jan 18;60(2):807-815. doi: 10.1021/acs.inorgchem.0c02859. Epub 2021 Jan 7.
The mechanism responsible for peptide bond hydrolysis by Co(III) and Cu(II) complexes with (oxa)cyclen ligands has been revisited by means of computational tools. We propose that the mechanism starts by substrate coordination and an outer-sphere attack on the amide C atom of a solvent water molecule assisted by the metal hydroxo moiety as a general base, which occurs through six-membered ring transition states. This new mechanism represents a more likely scenario than the previously proposed mechanisms that involved an inner-sphere nucleophilic attack through more strained four-membered rings transition states. The corresponding computed overall free-energy barrier of 25.2 kcal mol for hydrolysis of the peptide bond in Phe-Ala by a cobalt(III) oxacyclen catalyst () is consistent with the experimental values obtained from rate constants. Also, we assessed the influence of the nature of the ligand throughout a systematic replacement of N by O atoms in the (oxa)cyclen ligand. Increasing the number of coordinating O atoms accelerates the reaction by increasing the Lewis acidity of the metal ion. On the other hand, the higher reactivity observed for the copper(II) oxacyclen catalyst with respect to the analogous Co(III) complex can be attributed to the larger Brönsted basicity of the copper(II) hydroxo ligand. Ultimately, the detailed understanding of the ligand and metal nature effects allowed us to identify the double role of the metal hydroxo complexes as Lewis acids and Brönsted bases and to rationalize the observed reactivity trends.
通过计算工具重新研究了 Co(III) 和 Cu(II) 配合物与 (oxa)cyclen 配体的肽键水解的机制。我们提出，该机制首先通过底物配位和溶剂水分子的酰胺 C 原子的外球攻击开始，该反应由金属羟基质子化作为广义碱辅助进行，其通过六元环过渡态发生。与涉及通过更紧张的四元环过渡态进行的内球亲核攻击的先前提出的机制相比，这种新机制代表了更可能的情况。通过钴(III)环糊精催化剂（）水解苯丙氨酸-丙氨酸中的肽键的相应计算的总自由能垒为 25.2 kcal mol-1，与从速率常数获得的实验值一致。此外，我们通过在（oxa）环糊精配体中系统地用 O 原子取代 N 原子来评估配体性质的影响。增加配位 O 原子的数量通过增加金属离子的路易斯酸度来加速反应。另一方面，与类似的 Co(III) 配合物相比，铜(II)环糊精催化剂表现出更高的反应性，可以归因于铜(II)羟基质子化的 Brönsted 碱度较大。最终，对配体和金属性质影响的详细了解使我们能够确定金属羟合复合物作为路易斯酸和 Brönsted 碱的双重作用，并合理化观察到的反应性趋势。
