Insights into the interaction mechanisms between mogrosides and sweet and bitter taste receptors obtained by integrating molecular docking and dynamics simulations

BACKGROUND: Mogrosides are gaining popularity as alternatives to sucrose due to their high-intensity sweetness, low caloric content, and associated health benefits; however, the flavor mechanisms of different mogroside types remain poorly understood. To investigate this, molecular docking, molecular dynamics (MD) simulations, and steered molecular dynamics (SMD) simulations were conducted to explore the interactions of 12 mogrosides with taste receptor type 1 member 2-member 3 (T1R2-T1R3) and bitter taste receptors (T2Rs). RESULTS: The docking results for T1R2-T1R3 suggested a strong correlation between docking scores and the sweetness intensity of mogrosides. Siamenoside I, iso-mogroside V, and mogroside V, among others, not only bound to the Venus flytrap-like domain (VFT) of T1R2-T1R3 but also interacted with the seven-transmembrane helix domain (TMD). The sweet mogrosides did not bind to T2Rs, and only two bitter mogrosides interacted with them. Molecular dynamics simulations confirmed the conformational stability of the receptor-ligand complexes obtained from docking. Steered molecular dynamics simulations demonstrated that sweeter mogrosides exhibited stronger binding and slower dissociation from T1R2-T1R3, whereas bitter mogrosides showed distinct binding strengths and durations across T2Rs (T2R46 > T2R14 > T2R4). CONCLUSION: Overall, these results indicate that the delayed sweetness onset, prolonged sweet aftertaste, and slight bitterness characteristic of mogrosides can be attributed to the indirect signaling role of the TMD of T1R2-T1R3, spatially restricted pocket, and interaction with T2Rs. This study advances knowledge of mogroside flavor mechanisms and provides a theoretical basis for their targeted modification.