Fig. 4.

Thermodynamic cycle used for calculating the free energy necessary for the guest to change protonation state while in complex ($\Delta G_{\text{complex}}^{\text{neutralize}}$), illustrated for a positively charged guest. To evaluate $\Delta G_{\text{complex}}^{\text{neutralize}}$ we first compute the free energy of binding of the charged guest ($\Delta G_{\text{bind}}^{+}$) and of the neutral guest ($\Delta G_{\text{bind}}^0$) to the host through DDM and evaluate the free energy of changing protonation state in bulk ($\Delta G_{\text{bulk}}^{\text{neutralize}}$) through QM calculations