Predictions for drugs that modulate channel gating versus agonist binding. (A and C) A drug binding element (D) was added to scheme I (Fig. 4 A) such that it interacts with either the main gate (scheme IV) or one of the agonist binding sites (scheme V). Elements are depicted as labeled circles, and interactions as lines connecting the pair of interacting elements (e.g., see Fig. 3). All model parameters are referenced with respect to the symbol of their associated elements such that α_i and β_i are the rate constants for element i, and Θ_ij, Λ_ij, and Λ_ji are the interaction factors between elements i and j (see Materials and methods and Eqs. 7–12). Model parameters for schemes IV and V are as described for scheme I, and drug binding/unbinding rates were set to α_D = 1 × 10⁸ M⁻¹s⁻¹ and β_D = 0.3 s⁻¹, as described in the Materials and methods. Drug-bound interaction factors for scheme IV: Θ_Dm = 2, Λ_mD = 2, Λ_Dm = 1. For scheme V: Θ_DA = 25, Λ_AD = 5, Λ_DA = 5. (B and D) Simulated normalized current responses to 4-ms (left) or 500-ms (right) pulses of 10 mM GABA in the absence (control) or presence of 1 µM drug for scheme IV (B) and scheme V (D). (E) Simulated peak open probability dose–response relationship for schemes I, IV, and V. The broken line depicts scheme IV normalized to the maximal peak open probability for scheme I.