Figure 2.

Simulating allosteric modulation of functional responses and the impact of different operational parameters on modulator potency curves. For all simulations, the orthosteric agonist was defined by pK_A = 6, log τ_A = 1, where basal = 0, E_m = 100, and n = 1. In these simulations, the maximum response to orthosteric agonist approaches the system E_m. The parameters governing the allosteric modulator are noted in the figure for each simulation; in all instances, affinity modulation was neutral (log α = 0) and allosteric agonism was negligible (log τ_B = −100). (a) Simulating the effect of a pure PAM with different degrees of efficacy cooperativity on the concentration–response curve to an orthosteric agonist. (b) From the simulations in panel a, we plotted the PAM potency at the EC₂₀ orthosteric agonist response. (c) We performed similar simulations where log β values were held constant (equal to 1), but the modulator affinity (pK_B) was changed to show the impact on PAM potency.