Charge-scaled cavities in polarizable continuum model: Determination of acid dissociation constants for platinum-amino acid complexes

Abstract

The main aim of this study is the calculation of acid dissociation constants of the products of cisplatin reaction with the amino acids cysteine and methionine. In the first step, a suitable procedure for the calculation of solvation Gibbs free energies is found, based on the comparison of the calculated and experimental pK(a)s of both amino acids and simple platinum complexes. The resulting approach combines the DFT/B3LYP density functional, 6-311++G(2df,2pd) basis set, the D-PCM formulation of the continuum solvation model, and modified UAHF cavities. Since the main area of applicability of the UAHF model is solvation of organic molecules, a minor modification of the UAHF algorithm was necessary to improve the accuracy when applying it to the transition metal complexes. Instead of the integer (or semi-integer) formal charges used in the original formulation, more realistic partial charges obtained from the electronic density using the NPA procedure are used to generate molecular cavity. All other parameters of the model remain unchanged. This simple modification of the UAHF model works markedly better than the original formulation. The root mean square error of calculated pK(a)s over a set of molecules including zwitterions and divalent diaquaplatinum cation is equal to 0.74. In the second step, pK(a)s of platinum amino-acid complexes with the total charge ranging from 0e to 2e were computed. It was found that the pK(a)s of all ionizable groups of both amino acids are highly variable among the complexes studied. They range from -5 (in complexes containing protonated thiol or carboxyl groups directly bonded to platinum) to 14 (in monodentate complexes containing a positively charged amino group, which is stabilized by intramolecular hydrogen bonds).