Calculations of aqueous pK a values have a long history in computational chemistry, with methods ranging from direct quantummechanical approaches for determining the free energy of protonated and deprotonated species in solution using explicit, implicit, or hybrid solvation models, to continuum electrostatics-based computations of relative pK a shifts, and empirical or rulebased algorithms, as summarized in a number of review articles, e.g. Alongi et al. ,and Liao et al. and in the SAMPL6 overview papers .