Reactions of cisplatin with cysteine and methionine at constant pH; a computational study

Abstract

Interactions of hydrated cisplatin complexes cis-[Pt(NH₃)₂Cl(H₂O)]⁺ and cis-[Pt(NH₃)₂(OH)(H₂O)]⁺ with cysteine and methionine in an aqueous solution at constant pH were explored using computational methods. Thermodynamic parameters of considered reactions were studied in a broad pH range, taking up to 4 protonation states of each molecule into account. Reaction free energies at constant pH were obtained from standard Gibbs free energies using the Legendre transformation. Solvation free energies and pK_a values were calculated using the PCM model with UAHF cavities, recently adapted by us for transition metal complexes. The root mean square error of pK_a values on a set of model platinum complexes and amino acids was equal to 0.74. At pH 7, the transformed Gibbs free energies differ by up to 15 kcal mol⁻¹ from the Gibbs free energies of model reactions with a constant number of protons. As for cysteine, calculations confirmed a strong preference for κS monodenate bonding in a broad pH range. The most stable product of the second reaction step, which proceeds from monodentate to chelate complex, is the κ²S,N coordinated chelate. The reaction with methionine is more complex. In the first step all three considered methionine donor atoms (N, S and O) are thermodynamically preferred products depending on the platinum complex and the pH. This is in accordance with the experimental observation of a pH dependent migration between N and S donor atoms in a chemically related system. The most stable chelates of platinum with methionine are κ²S,N and κ²N,O bonded complexes. The comparison of reaction free energies of both amino acids suggests, that the bidentate methionine ligand can be displaced even by the monodentate cysteine ligand under certain conditions.