Exploring the Mechanism of Umami Peptide Binding with the T1R1/T1R3 Receptor via Molecular Dynamics Simulations

The Pacific oyster (Crassostrea gigas) is well known for its pronounced umami taste. Here the interaction between the T1R1/T1R3 taste receptor and three oyster-based peptides, namely, FLNQDEEAR (FR-9), EEFLK (EK-5), and FNKEE (FE-5), was investigated via molecular docking and molecular dynamics (MD) simulations, as well as molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) and residue–residue contact score (RRCS) analyses. A full-length human T1R1/T1R3 heterodimer was constructed with AlphaFold3. MD simulations indicated that the binding of FR-9 led to a large structural fluctuation, a large radius of gyration, and a large solvent accessible surface; on the contrary, FE-5 yielded the most stable receptor–ligand complex. The MM-PBSA analysis showed that the binding free energies of the three peptides were in the order of FR-9 > EK-5 > FE-5. The RRCS analysis indicated that RRCS values per residue were in the order of FR-9 < EK-5 < FE-5, in line with the reported umami score, and that the highest taste score of FE-5 originated from the hydrophobic interactions between Glu301 (receptor) and Phe1 (ligand) as well as the salt bridges between arginine (Arg277 and Arg307, receptor) and glutamic acid (Glu4 and Glu5, ligand) residues. These findings show that structural stability and residue contact density were more informative than binding affinity for distinguishing the taste intensity of umami peptides.