Transient formation of supramolecular complexes between hyaluronan and oligopeptides at submicromolar concentration.

Charged polymer interactions govern biological and technological processes by altering the structure and dynamics of surrounding water. Studying these interactions across a broad concentration range is challenging, particularly at submicromolar levels where traditional methods lack sensitivity or molecular resolution. Here, we investigate interactions between hyaluronan (HA), a biologically and technologically relevant polymer, and model oligopeptides-nonaarginine, nonalysine, and nonaglycine. By combining angle-resolved second harmonic scattering (AR-SHS), dynamic light scattering, nuclear magnetic resonance, and all-atom molecular dynamics simulations, we resolve the molecular-scale mechanisms and structure of HA-peptide interactions. Our findings reveal selective, multivalent binding between HA and cationic peptides, inducing solvent and solute restructuring and nanoscale clustering. Simulations provide atomic-level insight, elucidating the transient nature of the interactions and highlighting the distinctive behavior of arginine-rich peptides. Our approach, integrating AR-SHS with simulations and routine techniques, offers molecular insights into polymer mixtures and a foundation for future studies of dynamic supramolecular systems in soft materials.