Decoding the Molecular Mechanism of Sweet Taste of Amino Acids by Their Intrinsic Properties and Interactions with Human Sweet Taste Receptor.

The molecular basis of sweet taste toward various amino acids has not been fully elucidated. In this study, by correlation of their sweetness intensities with molecular properties, it is revealed that hydrophobic or dispersion force between side chains and sweet taste receptor (Tas1R2/Tas1R3) plays a prominent role for eliciting sweetness. Furthermore, the interaction modes of 13 amino acids with receptor indicate that amino (AH) and carboxyl (B) glucophores of different amino acids interact with identical residues of receptor, while the hydrophobic side chains (X glucophores) conduct distinct topological orientations with receptor, determining their chirality selection and sweetness intensities. Molecular dynamics analysis shows that sweet d‐amino acids move toward the hydrophobic transmembrane domain during activation with more contact numbers with receptor than nonsweet l‐amino acids, providing a mechanistic elucidation of previous inconsistent sensory evaluation results of specific amino acids. Moreover, by comparison with the interactions of a dipeptide sweetener, aspartame with Tas1R2/Tas1R3 and nonsweet l‐glutamate with class C G protein‐coupled receptors, we conclude that a complementary interaction mode with both hydrophilic and hydrophobic contacts accounts for the molecular origin of their sweet taste, presenting in‐depth insights and valuable guidelines for further molecular designs or modifications of amino acids‐derived sweeteners. [ABSTRACT FROM AUTHOR]