Prediction of pK_a Using DFT: the Nicotianamine Polyacid Example

The determination of pK_a values for molecules containing multiple acidic groups in solution is challenging both experimentally and theoretically. We propose a general method to obtain these values by combining a graphical analysis based on a predominance diagram, for amino acids and nicotianamine polyacid, with first principle DFT calculations. Implicit and semiexplicit water solvent models were included to account for solvation. This strategy enables the investigation of the protonation states of compounds containing acidic moieties in solution depending on the pH domain. The method was first validated on a set of amino acids with pK_a values calculated with an accuracy within 0.5-1.0 pK_a unit and then on the chalenging nicotianamine polyacid with six pK_a values. This approach is particularly well suited for such a complex system including both zwitterionic structures and unknown experimental pK_a values.