Structural Insights into the Interaction Between a Core-Fucosylated Foodborne Hexasaccharide (H₂N₂F₂) and Human...

Human noroviruses are the leading cause of foodborne gastroenteritis worldwide. Accumulating evidence suggests that food matrices containing fucosylated or histo-blood group antigen (HBGA)-like glycans may facilitate viral attachment and persistence, yet the molecular mechanisms underlying these interactions remain unclear.

In this study, we performed a comparative computational analysis of norovirus-glycan interactions by integrating AlphaFold3-based structure prediction, molecular docking, and molecular dynamics simulations. A total of 182 P-domain models representing all genotypes across five human norovirus genogroups (GI, GII, GIV, GVIII, and GIX) were predicted and docked with a lettuce-derived core-fucosylated hexasaccharide (H₂N₂F₂) previously identified by our group. The three complexes exhibiting the most favorable docking energies were further examined using 40 ns molecular dynamics simulations, followed by MM/GBSA binding free energy calculations and per-residue decomposition analyses.

Docking results indicated that the majority of modeled P proteins were able to adopt energetically favorable interaction poses with H₂N₂F₂, with predicted binding energies ranging from -3.7 to -7.2 kcal·mol^-1. The most favorable docking energies were observed for GII.6_S9c_KC576910 (-7.2 kcal·mol^-1), GII.3_MX_U22498 (-7.1 kcal·mol^-1), and GII.4_CARGDS11182_OR700741 (-6.8 kcal·mol^-1). Molecular dynamics simulations suggested stable ligand engagement within canonical HBGA-binding pockets, with recurrent residues such as Asp374, Gln393, and Arg345 contributing to electrostatic and hydrophobic interactions, consistent with previously reported HBGA-binding motifs. MM/GBSA analyses revealed comparatively favorable binding tendencies among these complexes, particularly for globally prevalent genotypes including GII.3, GII.4, and GII.6.

This work provides a large-scale structural and energetic assessment of the potential interactions between a naturally occurring lettuce-derived fucosylated hexasaccharide and human norovirus P domains. The results support the notion that core-fucosylated food-associated glycans can serve as interaction partners for diverse norovirus genotypes and offer comparative molecular insights into glycan recognition patterns relevant to foodborne transmission. The integrative AlphaFold3-docking-dynamics framework presented here may facilitate future investigations of virus-glycan interactions within food matrices.