Indeed, this could result in a more challenging resolution of "the pK a "; however, such interactions may provide insight into a reaction mechanism or suggest the functional importance of a residue pair. In these scenarios, a modified HH-curve may still yield two clear inflection points; however, the assignment of pK a values to specific residues could remain a challenge. Moreover, the protonation probability of a coupled residue, although potentially described by an HH-curve, is nonetheless a composite probability of microstates. As Edsall and co-workers, and more recently G. Matthias Ullmann and co-workers have helped formalize, these states are in a pH-dependent equilibrium with each other and collectively comprise the macroscopic probability observed experimentally. This knowledge gap between the measurable macrostates and the cryptic microstates suggests a potential role for theoretical and computational methods, which may help to resolve both the macroscopic pK a and the microscopic pK a values.