Figure 11.1 Thermodynamic cycle for pK calculations

Perform mean-field optimization at different pHs, using rotamers for both the protonated and deprotonated forms.
The pH-dependent ∆G^protonation_water energy penalizes the disfavored form at a given pH. This considers the intrinsic chemistry of the protonation reaction, and is modeled by the N-methylacetemide (NMe) model compound values.
The ∆G^protein->NMe transfer energies are calculated using the energy function with protein and model-compound structures.
The pH at which P(protonated) = P(deprotonated) for a sidechain is the apparent pK for that group.