Understanding the molecular mechanism of umami recognition by T1R1-T1R3 using molecular dynamics simulations

Taste receptor T1R1-T1R3 can be activated by binding to several natural ligands, e.g., L-glutamate and 5’-ribonucleotides etc., thereby stimulating the umami taste. The molecular mechanism of umami recognition at an atomic level, however, remains elusive. Here, using homology modeling, molecular docking and molecular dynamics (MD) simulations, we investigate the effects of five natural umami ligands on the structural dynamics of T1R1-T1R3. Our work identifies the key residues that are directly involved in recognizing the binding ligands. In addition, two adjacent binding sites in T1R1 are determined for substrate binding, and depending on the molecular size and chemical properties of the incoming ligand, one or both these binding sites can be occupied. More interestingly, the binding of varied ligands can lead to either closing or opening of T1R1, based on which, we further classify the five ligands into two groups. This different binding effects are likely associated with the distinct umami signals stimulated by various ligands. This work warrants new experimental assays to further validate the theoretical model and provides guidance to design more effective umami ligands. Author summary Umami, as the fifth basic taste, is induced by umami substances from the natural food, such as L-glutamate, 5’-ribonucleotides, and peptides etc. These umami substances are widely added to foods as flavor enhancers to promote food quality. However, although extensive experimental and theoretical studies have been devoted to revealing the recognition mechanisms of the taste receptor T1R1-T1R3 to the umami ligands, the detailed molecular mechanism is still unknown, largely due to the lack of the receptor structure. Here, using a new template structure different from the former theoretical studies, we constructed a more accurate homology model of T1R1-T1R3. Based on this receptor model, combined with molecular docking and MD simulations, we investigate how different ligands with varied molecular size and chemical groups might affect the dynamics of T1R1. Our work provides the structural basis for relating the dynamics of umami receptor induced by varied ligands to the resulting umami signal.