Fig. 7.

Unbinding paths and critical residue interactions along the dissociation pathways for salmeterol, formoterol, and salbutamol. (A–C) Dissociation paths for salmeterol, formoterol, and salbutamol, respectively. Salmeterol dissociates into the aqueous bulk and spends a transient period there before partitioning into the membrane near the receptor. Formoterol and salbutamol dissociate into the aqueous bulk surrounding the extracellular loop region. The start, intermediate, and final poses of the molecules are represented as density maps in red, gray, and blue colors, respectively. (D–F) Critical residues in contact with the ligands at their bound states and along the dissociation path. (G–I) Pie charts representing residues from various TMHs and ECL2 and the fraction of simulation time (percent occupancy) during which they are within 4 Å of the ligands.