Identification of novel sweet-enhancing peptides from yesso scallop (Mizuhopecten yessoensis) based on AlphaFold2-multimer modeling, molecular simulation, and quantum chemistry.

BACKGROUND

Yesso scallop contains many bioactive peptides and may serve as a promising source of sweet-enhancing peptides. The objective of the present work was to screen sweet-enhancing peptides using virtual screening, molecular simulation, and sensory evaluation.

RESULTS

Two structural models of the sweet taste receptor T1R2/T1R3 were constructed using AlphaFold2-multimer (AFM-T1R2/T1R3) and Swiss Model (SM-T1R2/T1R3). Based on a comprehensive evaluation of HADDOCK scores and conformational stability, the AFM-T1R2/T1R3 model demonstrated significantly superior molecular docking performance compared to the SM-T1R2/T1R3 model. Through virtual screening, 28 candidate peptides were obtained, from which three peptides (EGF, NCW, and ADM) with sweet-enhancing activity were finally selected after combining molecular docking and in vitro validation. E-tongue analysis showed that ADM exhibited the strongest sweetness, while sensory evaluation indicated that NCW had the most pronounced sweet-enhancing effect, and EGF possessed the lowest sweetness perception threshold (0.40 mmol L-1). Quantum chemical calculations confirmed the sweet-enhancing activity order as NCW > ADM > EGF, with Trp, Glu, and Ala identified as key active residues mediating peptide-receptor interactions. Molecular dynamics simulations revealed that the complexes formed by NCW and ADM with T1R2/T1R3 exhibited high stability and tight binding, with root-mean-square deviation fluctuations of around 0.2 nm. Combined with hydrogen bond and radius of gyration results, NCW demonstrated superior binding characteristics.

CONCLUSION

This study successfully applied the AlphaFold2-multimer model integrated with molecular simulation techniques to virtually screen and elucidate the molecular interaction mechanisms of potential sweet-enhancing peptides. This work provides a theoretical foundation for the further development of yesso scallop-derived sweet-enhancing peptides. © 2026 Society of Chemical Industry.