Rapid voluntary movement relies on post-synaptic acetylcholine receptors (AChRs) to detect nerve-released ACh, open an intrinsic ion channel and initiate muscle contraction. Long-standing questions include how the conformation of the AChR changes when ACh is bound, how the local conformational change is transmitted to the ion channel, and how these conformational changes correspond to steps in a physical reaction mechanism. To address these questions we combined high resolution structural data with molecular dynamics (MD) simulations, recordings of single channel currents through normal and mutant AChRs and fitted kinetic mechanisms to single channel dwell times. MD simulations of the related ACh binding protein reveal that at the periphery of the ACh binding site, a hairpin loop called the C-loop maintains an uncapped conformation in the absence of ACh, but in its presence changes to a capped conformation that envelops the bound agonist (1). After applying steered MD simulations to the AChR to accelerate capping of the C-loop, we find that the outer lumen of the channel widens while the inner lumen remains unchanged, and in parallel, the permeability to sodium ions increases to an extent that mimics the experimentally measured single channel conductance (2). To delineate how agonist-mediated conformational changes are transmitted to the ion channel, we focused on the region separating the ligand binding and ion channel domains, and evaluated coupling free energies between pairs of residues based on the cryo-EM structure of the Torpedo AChR (3) and high resolution structures of bacterial homologs of the AChR (4). We find that an invariant Arg residue shows strong energetic coupling to conserved Glu residues stemming from inner and peripheral β-sheets from the binding domain, and that residues from this assembly of loops couple to residues from the top of the pore domain (5). Thus housed within the hydrophobic core of the α-subunit, pairwise electrostatic interactions unite loops from three distinct regions of the ligand binding domain and positions them in register with the top of the ion channel. The process of AChR activation was classically described by del Castillo and Katz who proposed that the closed AChR with ACh bound makes a direct transition the open state. However, recent findings identified an intermediate closed state, and showed that the rates of the subsequent channel opening and closing steps were similar for agonists with widely differing efficacies (6). Furthermore, in AChRs with hydrophilic substitutions in the pore, these gating rate constants were similar for spontaneous as well as ACh-mediated channel openings (7). The intermediate closed state was thus proposed to be a state in which the AChR was primed for channel opening. In light of the conformational dynamics of the C-loop, we tested the possibility that capping of the C-loop primed the AChR channel for opening. After engineering cysteine residues, one at the tip of the C-loop and another at the opposing face of the binding site, chemical oxidation produced channel opening episodes that mimicked those produced by ACh, but were reversed by addition of reducing agent (7). Thus a change in binding site conformation primes the AChR channel for opening in a process that endows ACh with high efficacy while preserving a rapid biological response.