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

Ruth Pachter1, Soo-Kyung Kim1, Yixin C Xu1

  • 1Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA, 91125, USA.

European Biophysics Journal : EBJ
|June 5, 2026
PubMed

Insights

AlphaFold2 (AF2) predictions accurately model G protein-bound bitter taste receptors (TAS2Rs), serving as valuable starting points for drug discovery. Molecular dynamics simulations further refine these structures for enhanced accuracy in developing new TAS2R-targeted therapeutics.

Area of Science:

  • Pharmacology
  • Structural Biology
  • Computational Chemistry

Background:

  • Bitter taste receptors (TAS2Rs) are G protein-coupled receptors (GPCRs) involved in detecting bitter compounds.
  • TAS2Rs are expressed in various human tissues and implicated in diseases like cancer, making them attractive drug targets.
  • Limited structural data exists for G protein-bound TAS2R complexes, hindering drug development.

Purpose of the Study:

  • To assess the accuracy of AlphaFold2 (AF2) predictions for G protein-bound TAS2Rs.
  • To investigate the utility of AF2 structures as starting points for drug discovery.
  • To determine the role of Molecular Dynamics (MD) simulations in refining TAS2R structures for drug design.

Main Methods:

  • Utilized AlphaFold2 (AF2) to predict structures of G protein-bound TAS2R14 and TAS2R46.
  • Compared AF2 predictions with existing cryogenic electron microscopy (cryo-EM) data.
  • Performed Molecular Dynamics (MD) simulations on AF2-predicted structures at different temperatures (85 K and 310 K).

Main Results:

  • AF2 predictions for TAS2R14 and TAS2R46 showed good agreement with cryo-EM determined structures.
  • AF2-predicted structures for all 25 TAS2Rs can serve as initial models for drug development.
  • MD simulations refined AF2 structures, with significant thermal fluctuations observed at 310 K compared to 85 K cryo-EM data.

Conclusions:

  • AF2-predicted structures offer a viable starting point for drug discovery when experimental structures are unavailable.
  • MD simulations are crucial for refining AF2 structures to achieve sufficient accuracy for drug design.
  • Combining AF2 predictions with MD simulations at physiological temperatures (310 K) provides a robust framework for TAS2R drug discovery.
Keywords:
AlphaFoldBitter taste receptorsCryo-EMG protein-bound GPCRMolecular dynamicsProtein structure

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