HA ⁴ model. (A) HA⁴ model in systematic representation. Equilibrium association constants for ligand binding, K_x (x = 1…32). For globally fitting, 16 such intimately coupled HA⁴ models with multiple combinations of mutated binding sites were combined with the comprehensive CHA⁴ model (Schirmeyer et al., 2021). Blue circles, ligand; white circles, empty binding site. The set of closed–open isomerizations on the bottom is valid for all HA⁴ models. For the single-, double-, and triple-liganded open channel the ligands are drawn below the channel cartoon to illustrate that there are 4, 6, and 4 options of occupancy (brackets). (B) HA⁴ model of A in cube representation. The closed–open isomerizations (E_x) were omitted for clarity. (C) 4-D model of A in cube representation with virtual equilibrium association constants, Z_x, specifying the virtual transitions from state 0.