posted on 2024-03-06, 22:16authored byJacqueline
C. Calderón, Passainte Ibrahim, Dorothea Gobbo, Francesco Luigi Gervasio, Timothy Clark
Free-energy profiles for the activation/deactivation
of the β2-adrenergic receptor (ADRB2) with neutral
antagonist and inverse
agonist ligands have been determined with well-tempered multiple-walker
(MW) metadynamics simulations. The inverse agonists carazolol and
ICI118551 clearly favor single inactive conformational minima in both
the binary and ternary ligand–receptor-G-protein complexes,
in accord with the inverse-agonist activity of the ligands. The behavior
of neutral antagonists is more complex, as they seem also to affect
the recruitment of the G-protein. The results are analyzed in terms
of the conformational states of the well-known microswitches that
have been proposed as indicators of receptor activity.