Molecular Aggregates of Wheat Starch–Protein Systems: Structural Disruption and Engineered Digestibility via Non‐Covalent Synergy

ABSTRACT Designing starch‐based foods with controlled digestibility is critical for addressing global health challenges like diabetes, yet the molecular mechanisms underlying starch–protein interactions remain poorly quantified. Here, we investigate how wheat starch (WS) interacts with distinct protein fractions—wheat globulin (Glo), gliadin (Gli), and glutelin (Glu)—to form molecular aggregates that modulate digestion. By integrating experimental analyses (FTIR, XRD, rheology) with molecular dynamics (MD) simulations, we demonstrate that Gli and Glu exhibit stronger non‐covalent binding to starch than Glo, driven by hydrophobic forces and hydrogen bonding. These interactions disrupt starch chain entanglement, reduce short‐ and long‐range structural order, and inhibit α‐amylase activity. At a 50:9 starch‐to‐protein ratio, Gli and Glu increased resistant starch content by 6.74% and 6.91%, respectively, outperforming Glo (2.96%). MD simulations quantified binding free energies (−107.67 kcal/mol for Gli, −99.50 kcal/mol for Glu), revealing electrostatic contributions from Glu's lysine/arginine residues and hydrophobic interactions in Gli. Notably, Glo and Glu synergistically inhibit amylase via mixed competitive/non‐competitive mechanisms. This work establishes a predictive framework for starch–protein aggregate design, bridging molecular interactions to functional outcomes. By elucidating how protein composition dictates digestibility, we advance strategies for engineering low‐glycemic‐index foods, offering transformative potential for nutrition and food science.