Definition of coupling. (A) Two particles, 1 and 2, each can exist in two states, R and A. Each of them have an intrinsic preference for one of the two states, which is determined by its intrinsic free-energy difference between the two states (represented by the solid arrows). There are four state-dependent interactions between them: the horizontal broken lines represent the “like state” interactions, θ_AA and θ_RR, which are the interactions when both particles are in the A or R states, respectively; the diagonal broken lines represent the “unlike state” interactions, θ_AR and θ_RA, which are the interactions when the particles are in dissimilar states. (B) The system in A is represented in a reaction scheme showing the transitions between the different states. Alongside each transition, its equilibrium constant is shown. K₁ and K₂ are the intrinsic activation constants of the two particles. The presence of the state-dependent interactions modifies each of the equilibrium constants, but the net free-energy difference (ΔG_net) between the doubly resting (ground) state, RR, and the doubly activated (final) state, AA, is determined by the intrinsic equilibrium constants and the like state interactions.