Theoretical Insights into the Mechanism of Selective Peptide Bond Hydrolysis Catalyzed by [Pd(H₂O)₄]²⁺

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(H₂O)₄]²⁺ (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(H₂O)₂{(Gly)-(Pro)-(Met-κS,κN)}]¹⁺ 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 ¹H 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 °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.