Efficiency Measures The Conversion Of Agonist Binding Energy Into Receptor Conformational Change (Vol 151, Pg 315, 2019

Receptors alternate between resting <-> active conformations that bind agonists with low <-> high affinity. Here, we define a new agonist attribute, energy efficiency (eta), as the fraction of ligand-binding energy converted into the mechanical work of the activation conformational change. eta 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 eta and the y intercept gives the receptor's intrinsic activation energy (without agonists; Delta G(0)). We used single-channel electrophysiology to estimate eta for eight different agonists and Delta G(0) in human endplate acetylcholine receptors (AChRs). From published equilibrium constants, we also estimated eta for agonists of K(Ca)1.1 (BK channels) and muscarinic, gamma-aminobutyric acid, glutamate, glycine, and aryl-hydrocarbon receptors, and Delta G(0) for all of these except K(Ca)1.1. Regarding AChRs, eta is 48-56% for agonists related structurally to acetylcholine but is only similar to 39% for agonists related to epibatidine; Delta G(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. values between 12% and 57% and Delta G(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.