Constant-pH Simulation of the Human β₂ Adrenergic Receptor Inactivation.

ABSTRACT: Understanding the molecular basis of pH-dependent G protein-coupled receptor (GPCR) signaling is crucial for comprehending physiological regulation and drug design. Here, we investigate the human β₂ adrenergic receptor (β₂AR), a prototypical GPCR whose function is sensitive to pH conditions. Employing extensive constant-pH molecular dynamics simulations, we provide a detailed atomistic characterization of β₂AR inactivation across physiologically relevant pH values (4-9). Our simulations reveal that β₂AR inactivation is closely linked to protonation events at critical residues, notably E268^6×30 involved in the ionic lock formation. Furthermore, we find that inactivation occurs without direct sodium binding to the ion-binding pocket arou

SUBMITTER: Ballabio F 

PROVIDER: S-EPMC12529767 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature