Ligand-Driven Dynamics of Human Taste Receptors by Molecular Modelling

The perception of taste is a prime example of complex signal transduction at the subcellular level, involving an intricate network of molecular machineries. The investigation of such machineries at the nanoscale is greatly empowered by the tools provided by Computational Molecular Modelling, which is the foundation of the present work, aimed at elucidating the molecular mechanisms at the root of taste transduction. As a matter of fact, taste receptors are highly specialized proteins driving the activation/deactivation of specific cell signaling pathways, ultimately leading to the perception of the five principal tastes, namely, bitter, salty, sour, sweet and umami. Notably, the latter two are both detected by similar class-C G-protein-coupled receptors (GPCRs), which are the main focus of the present study. More in detail, the sweet and umami taste receptors’ extracellular ligand-detecting heterodimer was investigated by means of computational modelling techniques, specifically aimed at elucidating the mechanisms of ligand-receptor binding and the protein activation mechanisms. Three-dimensional atomistic models of said receptors were built by homology modeling techniques, starting from five experimentally-solved structures of a fish taste receptor. The difference between the two receptors lies in their alpha subunit, only sharing a 37,92% identity between the two. The obtained models were subsequently refined by Molecular Dynamics (MD) simulations, which allowed for the characterization of their conformational peculiarities and dynamics. After docking experimental binders, i.e. sucrose and glutamate, to the respective sweet and umami receptors, long MD simulations were performed in order to elucidate the structural and functional effects exerted by the presence of ligands. The alpha subunit is found to undergo the most relevant conformational alterations if compared to the homologous beta subunit, and the presence of ligands actively alters the exploration of the conformational space, modifying the twisting and hinging angles between the two receptors’ subunits. Future studies might readily employ the methodologies and platforms of the present work to investigate other taste receptors, e.g. for bitter taste, and to study the behavior of sweet and umami receptors more in depth, especially in terms of the interaction between the extracellular ligand-recognizing heterodimer and the transmembrane domain.