Abstract:
The structural dynamics and interaction mechanisms of the TAS2R4 and TAS2R14 bitter taste receptors enhance the palatability of the natural, zero-calorie sweetener Stevia Rebaudiana. Despite the health benefits of stevia, its bitter taste, due to the activation of TAS2R4 and TAS2R14 receptors, limits its acceptance, especially in diabetics who need an effective sugar substitute. The problem statement focuses on improving stevia's bitter sensory profile to promote better dietary adherence. Several studies have contributed to identifying research gaps, including a limited understanding of the molecular interactions between steviol glycosides and human bitter taste receptors and a lack of comprehensive research on natural sweetener substitutes that address taste modulation at the molecular level. Herein, molecular modeling strategies were used to predict the 3D structure of TAS2R4 and the TAS2R14 structures which were further refined by loop modeling and energy minimization. Molecular docking studies identified key residues involved in ligand binding, with BCML, GABA, and GIV3727 emerging as important blockers. Detailed 2D and 3D visualizations of these interactions provided deep insight into the molecular basis of taste receptor inhibition. MD simulations confirmed these results by showing stable protein-ligand interactions over 100 ns, with RMSD and RMSF analyses, highlighting the conformational stability and flexibility of the complexes. TAS2R14 was similarly analyzed, confirming stable binding interactions and identifying key residues through docking and MD simulations. The results showed that the identified inhibitors, BCML, GABA, and GIV3727, effectively interact with TAS2R4 and TAS2R14, stabilizing the receptor-ligand complex and possibly reducing the bitter taste of stevia. Ramachandran plots for both the initial and final frames of the simulations indicate a high percentage of residues in favored regions, ensuring the structural integrity of the models. A validated pharmacophore model and molecular docking identified five natural compounds as potential TAS2R4 and TAS2R14 modulators, showing key binding site similarities to known inhibitors. The study identified five natural compounds as promising modulators of TAS2R4 and TAS2R14, providing a strong basis for future therapeutic development targeting these receptors.
