<i>In silico</i> identification and action mechanism of potential sleep-promoting peptides from egg proteins

Abstract Chronic insomnia can significantly impair cognitive function and emotional stability, and may even trigger or exacerbate systemic health issues such as cardiovascular disease and metabolic disorders. This study intended to identify novel potential sleep-promoting peptide candidates from egg proteins and elucidate their molecular mechanisms with γ-aminobutyric acid (GABA) type-A receptor (GABAAR), orexin 2 receptor (OX2R), and nociceptin/orphanin-FQ receptor (NOPR). Through in silico hydrolysis, water solubility and toxicity prediction, molecular docking, and molecular dynamics simulations, six novel potential peptide candidates were identified. Among these, QPVDNY exhibited the strongest binding affinities of –9.2, –9.7 and –9.0 kcal/mol with GABAAR, OX2R and NOPR, respectively. Subsequently, peptide LKPIAAEVY showed affinities of –8.6, –9.7 and –8.2 kcal/mol with the three receptors, respectively. Molecular docking results showed that peptides QPVDNY and LKPIAAEVY bound to residues Leu259, Thr256, His267, and Glu270 of GABAAR via π-alkyl and hydrogen bonds, formed π-alkyl bonds with residues Pro131, Cys107, Phe227, Phe346 and His350 of OX2R. In addition, these two peptides formed π-alkyl bonds and hydrogen bonds with residues Val283, Met134 and Tyr131 of NOPR, meanwhile, they bound to residue Asp130 of NOPR via hydrogen bonds and a salt bridge. Molecular dynamics simulations confirmed the good stability of the peptide-receptor complexes. This study identifies novel potential candidates for natural sleep-promoting foods and establishes an efficient approach for screening food-derived bioactive peptides.