In 2007, Müller and co-workers at Hoffmann-La Roche found unusual pKa effects in a series of stereochemically complex tricyclic thrombin inhibitors. This paper has subsequently been used as a test set for pKa prediction and has been observed to be particularly challenging in several different cases. We too found this to be a challenging dataset, with an MAE of 1.63 and an RMSE of 1.94. Visual analysis of the predictions shows that Rowan pKa systematically overestimates the pKa of the tricyclic amines and that substantial predictive power remains despite the high error, as demonstrated by the moderate r 2 and τ values. These errors may arise in part from the fact that the conjugate acid of these amines is doubly cationic, which may lead to inaccuracies in the computed free energy of solvation. We next examined the ability of Rowan pKa to predict the pKa of macrocyclic peptides. Macrocyclic peptides inhabit different conformations from their linear congeners and frequently possess markedly different pKa values, with significant consequences for solubility and bioavailability. In 2018, Yudin and co-workers reported that the pKa of reduced amide bonds adjacent to oxadiazole rings was lowered in macrocycles, which they attributed to intramolecular hydrogen bonding that stabilizes the neutral amine. Rowan pKa was able to recapitulate the observed trend in pKa values (Figure ), which would be considerably more challenging for QSPR-type methods that do not explicitly consider conformational effects. Finally, we explored the suitability of Rowan pKa as a highthroughput method for pKa prediction. We selected the first 100 rings from Peter Ertl's recently published library of medicinal chemistry-relevant ring systems as a test set (15.5 atoms/molecule on average) and investigated whether the accuracy of the conformation search/refinement process could be further reduced to increase throughput without significantly hurting the workflow's accuracy. Two modes with reduced conformer searching were eventually developed: the key changes made for each new mode are summarized in Table . Modest gains in efficiency are possible, but at the cost of significantly increased error: if multiple low-energy conformers exist, these data suggest that they should be included. a Timings reported for an EC2 c5.2xlarge instance.