Efficiency measures the conversion of agonist binding energy into receptor conformational change

Receptors alternate between resting↔active conformations that bind agonists with low↔high affinity. Here, we define a new agonist attribute, energy efficiency (η), as the fraction of ligand-binding energy converted into the mechanical work of the activation conformational change. η depends only on the resting/active agonist-binding energy ratio. In a plot of activation energy versus binding energy (an “efficiency” plot), the slope gives η and the y intercept gives the receptor’s intrinsic activation energy (without agonists; ΔG(0)). We used single-channel electrophysiology to estimate η for eight different agonists and ΔG(0) in human endplate acetylcholine receptors (AChRs). From published equilibrium constants, we also estimated η for agonists of K(Ca)1.1 (BK channels) and muscarinic, γ-aminobutyric acid, glutamate, glycine, and aryl-hydrocarbon receptors, and ΔG(0) for all of these except K(Ca)1.1. Regarding AChRs, η is 48–56% for agonists related structurally to acetylcholine but is only ∼39% for agonists related to epibatidine; ΔG(0) is 8.4 kcal/mol in adult and 9.6 kcal/mol in fetal receptors. Efficiency plots for all of the above receptors are approximately linear, with η values between 12% and 57% and ΔG(0) values between 2 and 12 kcal/mol. Efficiency appears to be a general attribute of agonist action at receptor binding sites that is useful for understanding binding mechanisms, categorizing agonists, and estimating concentration–response relationships.