Sweet Taste and Chirality – Interactions of Sugars and Amino Acids with the Human Sweet Taste Receptor

Sweet taste is one of the primary determinants of food preference and intake and has a huge impact on health and global economy, leading to constant search for cost effective, healthy, novel sweeteners. Here we analyze the molecular recognition of ligands by the sweet taste receptor, focusing on the role of chirality in the sweetness of sugars and amino acids. The sweet taste receptor is comprised of Tas1R2 and Tas1R3 monomers. Homology modeling of the extracellular Venus Fly Trap (VFT) domain of the receptors was based on the metabotropic glutamate receptors (mGluR) Xray structures. Next, an automated docking campaign to screen the models against their known ligands (and decoys with similar physicochemical properties but dissimilar 2D topologies) was carried out. Analysis of over 20,000 compounds showed higher ranking of true positives compared to decoys in 95% of the cases, implying high sensitivity and specificity of the models. Ligand-receptor interactions analysis was validated using existing data about sweet compounds. Interestingly, the binding site was found to be semi-symmetrical around a hinge (Arg385). The predicted interactions are compatible with high specificity for enantiomers of amino acids, along with lack of stereospecificity towards L- and D-sugars. Our results successfully post-dicted recently patented sweeteners, providing an efficient protocol for prospective prediction of novel sweeteners by in-vitro screening.