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

Abstract 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.