Hydrolytic: cleavage of the oligopeptides Ace-Ala-Lys-Tyr-Gly similar to Gly-Met-Ala-Ala-Arg-Ala and Ace-Lys-Gly-Gly-Ala-Gly similar to Pro-Met-Ala-Ala-Arg-Gly by [Pd(H2O)(4)](2+) was theoretically investigated by using molecular dynamics simulations and quantum mechanical calculations. The Pd anchorage to the peptide sequence is crucial to provoke the cleavage of the second bond upstream from the anchored methionine. For both cases, the most favorable reaction mechanism is a three-step route. The first step coincides with the experimental suggestion found for the Gly similar to Pro-Met sequence on a cleavage caused by an external attack of a water molecule to a complex in trans conformation of the scissile Gly similar to Gly and Gly similar to Pro peptide bonds. However, our results uncover the important role played by the presence of a Pd-coordinated water molecule, which simultaneously interacts with the carbonyl oxygen atom of the Gly amino acid in the Gly similar to Gly and Gly similar to Pro bonds. In accordance with experimental facts, the rise of the hydrolysis reaction rate when the Pro amino acid is located in the scissile peptide bond was also corroborated. The findings obtained at a molecular level from the present computations not only are relevant to rationalize the previously reported experiments but also could be of importance in designing new Pd(II) complexes for the regioselective cleavage of peptides and proteins.