Extended Data Fig. 4: Modes and energetics of psychedelic binding to TrkB.

a, Binding free energies (ΔG ± s.e.m.) and the ranges for the corresponding dissociation constants are given for the drugs (neutral and protonated forms) and the WT and mutant variants (Y433F, V437A) of TrkB TMD dimers. CAR: cabergoline; DHE: dihydroergotamine. b, Representative MD snapshot showing the binding pocket for neutral LSD (purple) in the extracellular-facing side of TMD dimer (gray). Side chains (yellow) of relevant binding site residues are displayed. c, d, Contact probability between the neutral LSD heavy atoms (c) and binding pocket residues (d). Residues of the second chain in the dimer are indicated with an apostrophe (‘). e, Distributions of TMD dimer C-terminal distance show that neutral LSD stabilizes the cross-shaped conformation of TrkB favorable for receptor activation in a 40 mol% CHOL membrane. Lines represent the mean distribution and bands represent the standard errors (n = 10 independent simulations). TMD conformations corresponding to indicated C-terminal distances and drug-bound states are shown in the inset. Representative MD snapshots are shown for TMD conformations corresponding to indicated C-terminal distances of drug-free and neutral LSD-bound states. f, Representative MD snapshot showing the binding pocket for lisuride⁺ (orange) in the extracellular-facing side of TrkB TMD dimer. g, h, Contact probability between lisuride⁺ heavy atoms (g) and binding pocket residues (h). i, Distributions of TMD dimer C-terminal distance show that lisuride⁺ stabilizes the cross-shaped conformation of TrkB favorable for receptor activation in a 40 mol% CHOL membrane. Lines represent the mean distribution and bands represent the standard errors (n = 10 independent simulations). TMD conformations corresponding to indicated C-terminal distances and drug-bound states are shown in the inset. Representative MD snapshots are shown for TMD conformations corresponding to indicated C-terminal distances of drug-free and lisuride⁺-bound states. Detailed statistics reported in Supplementary Table 1.