Details of G-protein coupled receptor activation via data-driven molecular modeling

G protein-coupled receptors (GPCRs) shift between inactive non-signalling states and active signalling states, to which intracellular binding partners can bind. Extracellular binding of ligands stabilizes different receptor states and modulates the intracellular response via a complex and not well understood allosteric process. Despite the recent advances in structure determination and spectroscopy techniques, a comprehensive view of the ligand-protein interplay remains a challenge. We have derived the activation free energy landscape of the β2 adrenergic receptor (β2AR) bound to ligands with different efficacy profiles in the presence or absence of intracellular binding partner using enhanced sampling molecular dynamics (MD) simulations, to understand their modulatory effect.