Theoretical calculations of stability constants and pKa values of metal complexes in solution: application to pyridoxamine–copper(ii) complexes and their biological implications in AGE inhibition

Abstract

Accurate prediction of thermodynamic constants of chemical reactions in solution is one of the current challenges in computational chemistry. We report a scheme for predicting stability constants (log β) and pKa values of metal complexes in solution by means of calculating free energies of ligand- and proton-exchange reactions using Density Functional Theory calculations in combination with a continuum solvent model. The accuracy of the predicted log β and pKa values (mean absolute deviations of 1.4 and 0.2 units respectively) is equivalent to the experimental uncertainties. This theoretical methodology provides direct knowledge of log β and pKa values of major and minor species, so it is of potential use in combination with experimental techniques to obtain a detailed description of the microscopic equilibria. In particular, the proposed methodology is shown to be especially useful for obtaining the real acidity constants of those chelates where the metal-ligand coordination changes as a result of ligand deprotonation. The stability and acidity constants of pyridoxamine-Cu(2+) chelates calculated with the proposed methodology show that pyridoxamine is an efficient scavenging agent of Cu(2+) under physiological pH conditions. This is of special interest as Cu(2+) overload is involved in the formation of advanced glycation end-products (AGEs) and their associated degenerative medical conditions.

Theoretical pKa calculations with continuum model solvents, alternative protocols to thermodynamic cycles

“…When a thermodynamic cycle is used, it is important to choose a reference species that bears the same global charge than the studied acid because the magnitude of the global charge is the most determining factor of the errors in the solvation energies. In the case of the isodesmic reaction, our studies show that the similitude of global charges between the studied acid and the reference species is not the main factor that determines the precision . Instead, the regression studies show that the precision of the calculated p K a values is related to the p K a difference between the studied acid and the reference species (Figs .…”

“…The application of the isodesmic reaction to other acid groups such as pyridines, phenols, and benzylamines shows similar behavior than the carbon acids . In all the three sets of molecules, the errors are low if the p K a values of the acids AH are close to those of the respective reference species but otherwise the predicted p K a 's are overestimated.…”

“…The data corresponding to benzylamines has been omitted due to the absence of a statistically significant number of data but it is available on Ref. . The linear regressions of the experimental p K a values with the calculated free energies for each set of molecules gives slope values of 0.56 and 0.52, respectively, for the pyridines and phenols.…”

Detecting copper toxicity in sediments: from the subindividual level to the population level

“…The increase in pyridoxamine could also be linked to copper toxicity as it forms complexes with Cu 2+ and Fe 2+ and is involved in hydroxyl radical scavenging, indicating another possible antioxidant response (Casasnovas et al . ). The amine‐containing metabolites that have responded here offer pathways that could prove useful to further investigate contaminant and toxicity responses in C. tepperi .…”

The complexation of metal ions with various organic ligands in water: prediction of stability constants by QSPR ensemble modelling

“…The stability constants are of great importance in biology [1,2], in medicine [2][3][4], in the environment [5][6][7] and in analytical chemistry [8,9] to control the metal-ion complexation. At present, linear free energy relationships [10], quantitative structure-property relationships (QSPR) [11,12] and quantum chemical modelling [13,14] are used for computational estimation of the stability constants. In the last decades, QSPR models are intensively developed for metal-ion binding with organic ligands in solutions .…”