P.I.: Sébastien Fiorucci
Jérôme Golebiowski, Serge Antonczak.
At the physiological level, sweet taste perception consists of a chemical stimulation of the T1R2-T1R3 gustatory receptor on the surface of the tongue sensory cells. These receptors belong to the class C G protein-coupled receptor (GPCR) family, for which very few experimental structures are solved. Molecular modeling is perfectly suited to provide relevant three-dimensional structures and to gain insights on the recognition of tasting compounds by receptors involved in chemical senses.
Understanding the Dynamics of the Sweet Taste Receptor.
Like all class C GPCRs, the structure of the sweet taste receptor is characterized by a large N-terminal part, called Venus Flytrap Domain (VFD), linked to the 7-TransMembrane region (7TM) by a Cysteine Rich Domain (CRD). Sweeteners have been shown to interact with the receptor according to different binding modes: natural agonists bind the orthosteric site located in the VFD of T1R2, sweet taste modulators interact within the 7TM cavity of T1R3 and sweet proteins may bind with the CRD of T1R3 or with the 7TM domain of T1R2. Molecular dynamic simulation will help to assess the binding affinity between sweeteners and the sweet taste receptor. Furthermore, molecular details of the mechanism for signal transduction from the ligand binding site in the VFD part to the cytosolic side of the 7TM domain remain to be elucidated.
Characterization of Sweet Properties and Identification of New Sweeteners.
Currently, more than 100 plant derived sweet compounds have been reported. For instance, small organic compounds from natural extracts of Lippia dulcis, Gycyrrhiza glabra or Stevia rebaudiana are known to elicit sweet perception. In silico screening experiments based on structure-taste relationships of molecules in selected plant metaboloms will be carried out to identify new interesting sweet taste compounds: sweeteners, inhibitors or sweet enhancers.
The challenge to build a Quantitative Structure Activity Relationships (QSAR) model is to link this large diversity of chemical structures to a unique activity, i.e. the activation of the sweet taste receptor. The molecular details used by machine learning methods will help analyze the physico-chemical properties of sweeteners.