Ligand-gated ion channels, including the acetylcholine receptors (AChRs), bind to cholinergic agonists (e.g., neurotransmitter acetylcholine) that triggers channel opening and conduction of ions. Agonist binding to the channel and the ensuing global conformational changes (‘gating’) are complex chemical processes. To gain insight into this process, we have devised methods to directly quantify the free energy changes and measure the structural dynamics in the receptor during ligand binding and channel gating. The major innovation of the method is to estimate the intrinsic channel gating (in the absence of any ligand) of a wild-type receptor by experimental methods.

By using a combination of thermodynamics, receptor engineering, single channel patch-clamp studies, kinetic modeling, and molecular dynamics (MD) simulations, we have been investigating the mechanism of ligand binding, channel gating, affinity, efficacy, and efficiency of neuromuscular and neuronal nicotinic AChRs. They are typical allosteric proteins and the principles learnt from these studies will be applicable universally to all allosteric proteins. Receptor efficiency is a novel parameter that defines the ‘suitability’ of a ligand to activate a receptor and may potentially aid in drug candidate screening. Two ligands with the same chemical core (e.g., a benzene ring), but different chemical adduct (e.g., SH vs. OH) may differ in their receptor efficiency. Our preliminary work suggests that efficiency is a universal attribute of the receptors and perhaps, depends on the structural alignment of the ligand in the binding pocket.