Energetics, RR, and magnitude of the control response for partial agonists co-applied with a positive allosteric modulator. (A) The graph shows the free energy change provided by the modulator (ΔG_M) that is required to triple the control response at different magnitudes of the control response (EC_agonist). The red dashed line describes the relationship for an agonist that at saturating concentration generates a response with a P_A of 0.5. The blue dash-dotted line describes the relationship for an agonist that at saturating concentration generates a response with a P_A of 0.25. The calculations were done using Eq. 7. (B) The relationships between the RRs and EC_agonist were calculated (Eq. 8) for the partial agonists, assuming the modulator contributes −1 kcal/mol of free energy change toward gating. The black solid lines in both panels are reproduced from Fig. 1 and illustrate the relationship for a fully efficacious agonist (at EC₁₀₀ P_A = 1).