Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, Florida 33146, USA.
Inorg Chem. 2010 Jan 4;49(1):38-46. doi: 10.1021/ic901071v.
In this study, mechanisms for the hydrolysis of the Gly-Pro bond in Gly-Pro-Met and Gly-Pro-His, the Gly-Sar bond in Gly-Sar-Met, and the Gly-Gly bond in the Gly-Gly-Met peptide catalyzed by Pd(H(2)O)(4) (I) have been investigated at the DFT level. In all cases, the optimized structure of the active bidentate complex, formed by the reaction of I with the substrate Pd(H(2)O)(2){(Gly)-(Pro)-(Met-kappaS,kappaN)} complex for the Gly-Pro-Met peptide, was found to exist in the trans conformation. This structure is in agreement with the experimentally measured TOCSY and ROESY (1)H NMR spectra. After the formation of this complex, the following two mechanisms have been proposed experimentally: (1) external attack mechanism and (2) internal delivery mechanism. The DFT calculations suggest that in the external attack mechanism the calculated barriers are prohibitively high (i.e., 50-70 kcal/mol) for the cleavage of all the peptide bonds, and therefore, this mechanism is ruled out. However, in the internal delivery mechanism, the bidentate complex is first transformed from the trans to the cis conformation. Here, the overall barriers for the hydrolysis of the Gly-Pro-Met, Gly-Pro-His, Gly-Sar-Met, and Gly-Gly-Met peptide bonds are 38.3, 41.4, 39.8, and 39.2 kcal/mol, respectively. These barriers are in much better agreement with the experimentally measured rate constants at pH 2.0 and at 60 degrees C. The substitution of Pd(II) with Pt(II) was found to make a negligibly small difference (0.53 kcal/mol) on the barrier for the cleavage of the Gly-Pro-His bond. These calculations indicate that after the creation of the active bidentate complex in the trans conformation the internal delivery mechanism is the most energetically feasible.
在这项研究中，我们在密度泛函理论（DFT）水平上研究了Pd(H(2)O)(4)（I）催化的 Gly-Pro-Met 和 Gly-Pro-His 中 Gly-Pro 键、Gly-Sar-Met 中 Gly-Sar 键以及 Gly-Gly-Met 肽中 Gly-Gly 键水解的机制。在所有情况下，通过 I 与底物Pd(H(2)O)(2){(Gly)-(Pro)-(Met-kappaS,kappaN)}复合物的反应形成的活性双齿配合物的优化结构，对于 Gly-Pro-Met 肽，被发现存在反式构象。该结构与实验测量的 TOCSY 和 ROESY（1）H NMR 谱一致。形成该配合物后，提出了以下两种实验机制：（1）外部攻击机制和（2）内部传递机制。DFT 计算表明，在外部攻击机制中，所有肽键的计算壁垒都非常高（即 50-70 kcal/mol），因此该机制被排除。然而，在内部传递机制中，双齿配合物首先从反式构象转变为顺式构象。在此，Gly-Pro-Met、Gly-Pro-His、Gly-Sar-Met 和 Gly-Gly-Met 肽键水解的总壁垒分别为 38.3、41.4、39.8 和 39.2 kcal/mol。这些壁垒与在 pH 2.0 和 60°C 下实验测量的速率常数更为一致。与 Pd(II)相比，Pt(II)的取代对 Gly-Pro-His 键断裂的壁垒影响可忽略不计（0.53 kcal/mol）。这些计算表明，在反式构象中形成活性双齿配合物后，内部传递机制是最具能量可行性的。
