Prediction of Absolute Hydroxyl pKa Values for 3-Hydroxypyridin-4-ones

pKa values have been calculated for a series of 3-hydroxypyridin-4-one (HPO) chelators in aqueous solution using coordination constrained ab initio molecular dynamics (AIMD) in combination with thermodynamic integration. This dynamics-based methodology in which the solvent is treated explicitly at the ab initio level has been compared with more commonly used simple, static, approaches. Comparison with experimental numbers has confirmed that the AIMD-based approach predicts the correct trend in the pKa values and produces the lowest average error (∼0.3 pKa units). The corresponding pKa predictions made via static quantum mechanical calculations overestimate the pKa values by 0.3-7 pKa units, with the extent of error dependent on the choice of thermodynamic cycle employed. The use of simple quantitative structure property relationship methods gives prediction errors of 0.3-1 pKa units, with some values overestimated and some underestimated. Beyond merely calculating pKa values, the AIMD simulations provide valuable additional insight into the atomistic details of the proton transfer mechanism and the solvation structure and dynamics at all stages of the reaction. For all HPOs studied, it is seen that proton transfer takes place along a chain of three H2O molecules, although direct hydrogen bonds are seen to form transiently. Analysis of the solvation structure before and after the proton transfer event using radial pair distribution functions and integrated number densities suggests that the trends in the pKa values correlate with the strength of the hydrogen bond and the average number of solvent molecules in the vicinity of the donor oxygen.