A unified molecular theory of sweet taste: revisit, update and beyond

The molecular mechanism for the generation of sweet taste is still elusive, mainly because there has no common feature revealed imparting sweetness to various sweeteners1-2, although many principles and models have been proposed to interpret their structure and activity relationships (SARs)3-8. In this research, the SARs of sweet compounds of widely different chemical families were surveyed from a "trace to the source" view on the molecular organization of their components and their interaction with the sweet taste receptor (STR). This leads to a disclosure of intrinsic connectivity patterns in both sweeteners and STR: charge complementarity and compatibility between components, which afford the complementary sweetener-receptor interaction that induces receptor activation, accounting for the molecular origin of sweet taste. Herein, the analogous topology between glucophores in sweeteners and its counterparts in receptor, and their befitting orientated interaction, which is the common molecular feature of sweeteners, are firstly revealed. This paradigm not only provides a meaningful framework and helpful guidelines for further exploring SARs and molecular modification/design of sweeteners, but also has significant implications to illuminate the underlying mechanisms of molecular origin/evolution of both sweeteners and sweet taste receptors.