Identification and inhibition mechanism of novel collagen-derived hyaluronidase inhibitory peptides

Given the rising incidence rate of chronic allergic diseases and the side effects of traditional anti-allergic drugs, this study aimed to identify novel hyaluronidase inhibitory peptides from various food-derived collagen by an integrated computational screening strategy with in vitro inhibitory activity verification, and to elucidate the inhibition mechanism of peptides based on the simulated dynamic characteristics, quantum chemistry calculation, and weak interaction analysis. Two potent hyaluronidase inhibitory peptides with non-toxicity, nonallergenicity, good water solubility, and good simulate gastrointestinal stability, that is, Pro-Gly-Pro-Ala-Gly-Arg (PGPAGR) from Nile tilapia and Gly-Pro-Ser-Gly-Pro-Arg (GPSGPR) from rainbow trout, Nile tilapia, donkey, bovine, and domestic pig, were identified with IC50 values of 11.98 +/- 0.42 mM, 13.64 +/- 0.21 mM, respectively. During the 100 ns dynamic interaction, two peptide-hyaluronidase complex systems both remained relatively stable. Additionally, the dynamic binding of these two peptides further enhanced the structural stability and compactness of hyaluronidase, and reduced the inverse movement between different residues of hyaluronidase. The results of residue free energy decomposition showed that residues Tyr75, Tyr202, Trp321, and Trp324 made prominent positive contributions to the binding of peptide GPSGPR, while residues Tyr202, Tyr247, and Arg265 made prominent positive contributions to the binding of peptide PGPAGR. The results of weak interaction analysis showed that hydrogen bond and van der Waals interactions were the dominant weak interaction types in the dynamic binding between the peptides and hyaluronidase. This study will provide theoretical basis and data support for the development of novel anti-allergic functional foods and drugs, and offer novel strategies for the prevention and improvement of allergic diseases.