Prism: pathway selection by φ. (A) Vertices, stable C, O, and D conformations; superscript A, agonist; lowercase letters, free energy changes (direction of arrow); dashed line, unused pathway. Independent energy changes are g, unliganded gating; b, agonist binding; d, desensitization. Binding energy is the same to D and O (twice that to C); agonists influence a reaction only by a binding energy change; other energies set by microscopic reversibility. In adult mammalian AChRs g = +8.3, d = −6.5 kcal/mol, so (g + d) = +1.8 kcal/mol (5% of unliganded receptors are D). Red, main path with a bound agonist: ^AD is connected to ^AO because here φ ∼ 1; blue, main recovery path without agonists; D is connected to C because here φ ∼ 0. (B) Landscape analogy. Top: Before the earthquake (the agonist), a hiker in the valley of D takes the easier, east trail to C (blue arrow). Bottom: An earthquake collapses only the west side of the range, to lower ^AD (and ^AO) valleys and west pass. The trail from ^AD to ^AO is the same as before the quake, but the unaltered east trail to ^AC is now disfavored. Not shown. The quake also levels the once-high pass between ^AC and ^AO (behind the central peak). After reaching ^AO, the hiker can cross readily back and forth along this “gating” trail, eventually to revisit ^AD by the easier west trail from ^AO (red arrow).