In most cases, it is safe to assume that the mutual dependence (or coupling) of a residue A and its protein microenvironment is small, and by simply assigning residues to the charge state most likely for a corresponding model compound in solution (e.g., capped peptide) at pH ≈ 7.4, we can assume pK a (protein) ≈ pK int . However, there are cases where this assumption will fail and a consideration of ∆G titr (pH), at least for nearby titratable residues, is necessary to correctly resolve pK a (protein).