Molecule SM06 can definitely be considered an outlier, not just due to the large discrepancy between our prediction and experiment, but also due to an ionizable group we did not properly identify (Figure ). In this case our predicted value of 3.94 ± 0.5 is matched with the experimental value 11.74 ± 0.01, as pointed out in Figure . This molecule contains three ionizable groups: the pyridine nitrogen base, the quinoline nitrogen base and the amide nitrogen either as a base at low pH or as an acid at high pH . We did not train our model to treat amides as either acids or bases (Section 2.1). Our model predicted the transition In order to improve our model, we consider how similar functional groups are represented in our training set and look to the literature to attempt to determine which microstate dominates at the 11.74 ± 0.01 transition. It seems probable that the deprotonation from +3 charge to +2 charge would occur well below pH2.0, outside the experimental range, and is most likely dom- ) RMSD = 1.9 ± 0.2 R 2 = 0.86 ± 0.03 Fig. These plots compare microscopic pK a predictions for all combinations of our model, SimulationPlus' pK a predictor and ACD Lab's pK a GALAS. We divide our predictions into two sets: One with predicted uncertainties less than two pK a units (orange squares) and greater uncertainties (blue circles). The shaded region indicates an agreement within 1pK a unit. Root Mean Squared Deviation (RMSD) and R 2 are reported for all pairs of points with the same statistics reported in parentheses for low uncertainty points where applicable. This plot shows our macroscopic pK a predictions compared to experiment. The shaded region represents agreement within 1pK a unit. The most significant outlier (SM06) is due to an acidic we did not identify as ionizable inated by the deprotonation of a charged and doubly protonated amide. The next transitions are less immediately obvious, so we look to our training set which contains meta-substituted bromo-pyridines and carboxamide pyridines, both with pK a s in the low 3s. It also includes several monoprotic quinoline derivatives with pK a s from 4.8 -5.5. One explanation for this large error could be that the carbonyl of the amide group could form an internal hydrogen bond stabilizing the proto-nated form of the quinoline and increasing its pK a .