Finally, we compute pK a values for these Cucontaining proteins. Prediction of pK a values is a notoriously difficult computational problem, but one where continuum solvation has historically played a role. Figure reports pK a values for each system in its flipped and unflipped form using various PCM-type boundary conditions. (Numerical data are provided in Table .) Experimental values, used here and in Ref. 107 to assess errors, are: pK a < 2 for 1E5Y and 2CAK, 131-135 pK a = 7.2 for 1ID2, 136 pK a = 4.4 for 1KDI, 124 and pK a = 4.8 for 1PZA. For each system except 2CAK, we see a considerable decrease in the predicted pK a upon application of any solvent model. Reduction in pK a upon solvation is expected based on stabilization of the charged species, and the one exception is also the only system to exhibit a negative pK a . This indicates that 2CAK is a much stronger acid than fern plastocyanin. Looking at the different solvation models, the best-performing one (as compared to experiment) is HetPCM with ε nonp = 10. However, all of the solvation models reduce the error as compared to the gas-phase result. Excluding fern plastocyanin (1KDI), which is the reference value, the average absolute difference from experiment, expressed in pK a units, is 4.6 (gas phase), 1.3 (isotropic PCM), 1.4 (HetPCM with ε nonp = 4) and 1.1 (HetPCM with ε nonp = 10). Expressed in energy units (∆G • ), both versions of HetPCM predict these values within 1.3 kcal/mol of experiment.