Results obtained with gas-phase (vacuum) boundary conditions are effectively useless, with average pK a errors that exceed 2 in most cases and exceed 6 in several cases. The largest differences with respect to experiment are for the enzyme 1PZA, which was also true in Ref. 107. (In the present work, the relaxed structure for 1PZA exhibits coordination distances to the Cu center that differ by only about 0.1 Å from those reported in Ref. 107.) Moreover, gas-phase calculations cannot rationalize differences in pK a upon imidazolium flipping. The differ-ence between the two acid forms (∆pK a ), averaged across the data set in Fig. , is ∆pK a > 1 for gas-phase calculations but ∆pK a < 1 for solvated calculations.