Molecular Dynamics Insights into TAS1R2 Transmembrane Domain Activation

Sweet taste receptors (STRs) are class C G protein-coupled receptors (GPCRs) that function as heterodimers of TAS1R2 and TAS1R3. These receptors possess multiple binding sites and can be activated by a wide range of sweet-tasting compounds. Interestingly, TAS1R2 alone or even its extracellular domain-truncated form (TAS1R2-TMD), can act as a functional receptor. Previous studies demonstrated that the sweetener S819 and the sweet inhibitor amiloride act through the transmembrane domain (TMD) of TAS1R2; however, the molecular mechanisms underlying these ligand-specific effects remain unclear, largely due to the historical lack of experimentally determined full-length STR structures. Recent breakthroughs in cryo-EM structural determination of the full-length TAS1R2/TAS1R3 complex now offer an unprecedented opportunity to elucidate receptor activation mechanisms at atomic resolution. In this study, we investigated ligand-induced conformational dynamics of hTAS1R2-TMD using microsecond-scale molecular dynamics (MD) simulations on three systems: hTAS1R2-TMD/S819 (agonist-bound), hTAS1R2-TMD/amiloride (antagonist-bound), and hTAS1R2-TMD (apo). Comparative analyses revealed that agonist and antagonist binding distinctly modulate key structural switches, including the conserved ionic lock (E6.35-R3.50), which stabilizes the inactive state and disrupts upon activation. Notably, we identified a novel salt bridge (D7.32-R3.32) that forms preferentially in the active state, potentially serving as a unique molecular switch for TAS1R2. Additional analyses uncovered ligand-specific rearrangements in hydrogen-bonding and hydrophobic interaction networks. These results provide atomistic insights into how agonists and antagonists differentially modulate TAS1R2 activation and lay a structural foundation for designing novel sweeteners and taste modulators.