Rate bias is sufficient to achieve coupled transport in the 8-state model. Four sets of simulations explore the independent and combined effects of substrate off-rates and alternating access rates on drug gradient (T_r) observed at steady state with a driving force ΔpH = 1. In the 8-state model, perfectly coupled transport will result in a 10-fold drug gradient at steady state: T_r = 10 in the case of antiport and T_r = 0.1 in the case of symport. The orange dashed line represents 80% of the maximum coupling efficiency for antiport; the pink dashed line represents 80% of the maximum coupling efficiency for symport. (A) When only alternating access rates are varied, skewing the relative rates of alternating access in the states critical for symport or antiport pathways by 25-fold (R_AA = 25 for antiport and 1/25 for symport) achieves ∼80% of the maximum coupling efficiency. R_AA is defined in Eq. 4. (B) When only substrate off-rates are varied, skewing the relative substrate off-rates for symport- and antiport-critical states by 630-fold (R_off = 630 for symport, 1/630 for antiport) is needed to achieve ∼80% of the maximum coupling efficiency if the alternating access rates are sufficiently slow (k_AA ≤ 1 s⁻¹, blue line). If the uniformly constant alternating access rates are faster than ∼10 s⁻¹ (orange, yellow, and purple lines), transport is less efficient and the antiport/symport phenotypes diverge in behavior. R_off is defined in Eq. 7. (C) Steady-state transport phenotypes are independent of drug concentration, regardless of alternating access rate. Lines for drug concentrations ranging from 1 nM to 50 mM lie on top of each other. (D) When both R_off and R_AA are varied simultaneously, less skewing of the relative rates is needed to achieve highly coupled transport. The colored lines reflect the effect of varying R_off at different values of R_AA (R_AA = 0.2, blue; 0.5, orange; 1.0, yellow; 2.0, purple; 5.0, green). For all simulations, k_AA = 1 s⁻¹. With R_AA = 5.0 favoring antiport (green), 80% of the maximum coupling efficiency is achieved with a ratio of off-rates of only R_off = 1/23.