Bitter taste TAS2R14 and TAS2R46 receptors bound to G proteins: comparison of cryo-EM, AlphaFold, and molecular dynamics structures.

Bitter taste type 2 G protein-coupled receptors (TAS2R GPCRs) detect bitter substances on the tongue, but they are also prevalent in tissues throughout the human body that play a role in cancer and other diseases, making them targets for pharmacological research. However, structural information on G protein (GP)-bound TAS2R complexes resolved by cryogenic electron microscopy (cryo-EM) is available for only 4 of the 25 TAS2Rs. Herein, we show that AlphaFold (AF) predictions of GP-bound TAS2R14 and TAS2R46 agree well with cryo-EM structure determinations, thus suggesting that the AF2 predicted structures for all 25 TAS2Rs could be used as starting points for drug development. Although useful starting points, we show that Molecular Dynamics (MD) studies are needed to refine the AF2 structures to get sufficient accuracy for drug design. We find that the MD simulations agree well with the cryo-EM structures at 85 K, but significant changes occur in the MD structures at 310 K that arise from thermal fluctuations frozen-out in the cryo-EM structure, making them far less pronounced at 85 K. We conclude that for TAS2Rs for which cryo-EM structures are not available, AF2 predicted structures followed by MD at 310 K provide a basis for TAS2R drug discovery.