Structure-based model of AChR gating. Eight components undergo local off↔on transitions (black↔red): five are protein (left labels) plus the agonist (black/red filled circle), ions (green filled circle), and water (blue). Only the end state C (all components off) and O (all on) structures are stable. The gate region can be a hydrophobic cluster (gray square), a bubble (red open circle), or water. The four, short-lived intermediate states of the TSE (T1–4) have a mixture of on/off components. The five steps in the opening process are M2M3–TBS click-and-hold, ECD twist, TMD tilt, gate dilate, and gate wetting (bubble collapse). The energy landscapes (Fig. 6 E and Fig. S2) calculated from phi and flip suggest that ECD twisting is the most energetically unfavorable step in the opening process. Channel closing is the reverse of opening and starts with (and is rate limited by) the spontaneous reformation of a gate bubble. Animations of this scheme at different time scales are shown in Video 1.
