Investigating mechanism of sweetness intensity differences through dynamic analysis of sweetener–T1R2–membrane systems

[Display omitted] •28 various sweeteners were investigated systematically.•The releasing of natural weak sweetness sweeteners from the VFT domain were observed.•Artificial high-intensity sweeteners almost formed “inhibitor” of sweeter receptor.•Van der Waals and hydrophobic interactions made much contribution on sweetness. Knowing the mechanism of action of sweet taste receptors is important for the design of new, healthy sweeteners. However, little is known about the structures and recognition mechanisms of these receptors. 28 sweeteners were assessed by molecular docking, and 8 typical sweeteners were chosen to construct sweetener–T1R2–membrane systems to analyze interactions between receptor and sweeteners. Natural sweeteners with low-intensity sweetness, such as fructose and xylitol, were released from the Venus flytrap domain at ∼30 ns, with displacements greater than 50 Å. In contrast, artificial neotame and advantame bound stably to the receptor, within 5 Å. Van der Waals interactions were significant in high-intensity sweetener systems, imparting an energy difference of over 15 kcal/mol between neotame (artificial sweetener) and fructose (natural). These results provide a deeper understanding of the mechanisms of sweetener function and offer a new direction for the design of sweeteners.