Insights into Promiscuous and Selective Nature of Human Bitter Taste Receptors by Molecular Modelling

The mammalian sense of taste, a crucial natural mechanism for the evaluation of healthy food and recognition of toxic substances, is the result of a complex, multiscale signal transduction process. From the molecular/subcellular point of view, taste receptors are highly specialized proteins that allow the activation or deactivation of signalling pathways and the consequent perception of the five basic tastes: sweet, umami, bitter, salty and sour. Among them, the bitter taste is the one developed by nature to allow screening food molecules against poisons. A number of 25 different human bitter taste receptors (TS2R) has been identified till now. However, our knowledge of bitter taste mechanisms is limited by a lack of experimental data concerning the above-mentioned machinery structural features. In this concern, computational molecular modelling represents a great opportunity to shed light on molecular mechanisms driving bitter taste transduction. Here, molecular mechanics and molecular dynamics (MD) have been considered for underlining specific differences and similarities among the 25 known bitter taste receptors. Existing bitter receptor homology models (source http://bitterdb.agri.huji.ac.il/dbbitter.php) were considered as the starting point of our research. Those models have been analyzed in terms of sequence identity and conformational stability and dynamics with specific attention to the ligand binding domains. Conformational Analysis empowered by dimensionality reduction techniques highlights how protein conformational features and collective modes help to discern between promiscuous or selective nature of the receptor. The interesting structure to function relationships identified in this work open up doors for further computational and experimental studies focused on screening the variety of existing bitter ligands on the basis of their ability to bind promiscuous and/or selective bitter taste receptors and their global effect on receptor activity.