3.2. Computational Details. Unless otherwise noted, all calculations were performed using HF theory for the solute, because solvation energies computed with continuum models are no more accurate when DFT is used instead. An exception is that B3LYP+D3(BJ) is used for applications to protein pK a prediction in Section 4 .5, as a more representative use case. Here, D3(BJ) indicates Grimme's dispersion correction based on Becke-Johnson damping. These calculations were performed using Q-Chem with integral screening thresholds and shell-pair drop tolerance set to τ ints = 10 -12 a.u., as appropriate for medium-size systems with diffuse basis functions. The SCF convergence threshold was set to τ SCF = 10 -8 E h . For molecular PCM calculations, the cavity surface is constructed using radii in eq. 23 and discretized using 110 Lebedev points per atomic sphere, in the case of hydrogen, and 194 points per sphere for other atoms.