Subtype-selective binding of milk β-casomorphins across the opioid receptor family revealed by molecular docking and molecular dynamics simulation

초록

β-casomorphins (BCMs) are opioid-like peptides produced during the digestion of β-casein in the gastrointestinal tract. They are also involved in other gastrointestinal and neurophysiological processes. Although the effect of BCM7 on the μ-opioid receptor (MOR) has been extensively studied, the molecular interaction mechanisms of other BCMs with different opioid receptors have not been elucidated. This study aimed to investigate the receptor-specific binding behavior of BCM3–BCM11 across the μ-, δ-, κ-, and nociceptin/orphanin FQ peptide (NOP) opioid receptors using structure-based computational approaches. Three-dimensional structures of BCM peptides were generated and subjected to a peptide docking analysis for each opioid receptor. Comparative analyses of docking scores and binding modes were performed to identify receptor-preferred BCM variants. The selected high-affinity complexes for each receptor were further evaluated using molecular dynamics simulations to assess their structural stability and dynamic behavior. Protein–ligand contact analyses were conducted to characterize the residue-level interaction patterns and interaction persistence over time. Docking analysis revealed pronounced receptor- and peptide-dependent binding profiles. BCM7 exhibited the strongest affinity for MOR, consistent with previous reports. Meanwhile, other receptors showed a preference for distinct BCM variants, including BCM6, BCM9, BCM10, and BCM11, depending on the receptor subtype. Molecular dynamics simulations indicated that the selected BCM–receptor complexes reached stable conformational states after equilibration. Hydrogen bonding, hydrophobic interactions, and water-mediated contacts collectively contribute to peptide stabilization; notable differences are observed in contact composition among receptor subtypes, reflecting subtype-specific recognition features. Overall, this study provides a comparative molecular framework for understanding how structurally diverse BCMs interact with members of the opioid receptor family. These findings demonstrate that BCM7 dominance is largely MOR-specific and that other BCM variants may preferentially engage non-MOR opioid receptors. These results highlight the importance of looking beyond BCM7 and considering both peptide diversity and receptor subtype specificity when investigating BCM-mediated signaling mechanisms.

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