Order of Message and Address Domain Engagement Determines Productive β-Endorphin Binding to the μ-Opioid Receptor

2026 · doi:10.64898/2026.02.06.704327
preprint OA: closed
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Abstract

ABSTRACT Understanding β -endorphin binding to the μ-opioid receptor ( μ OR) is crucial for designing safer analgesics. The peptide comprises a message domain mediating activation and an address domain conferring selectivity. Using 1,000 independent CABS-dock simulations, without prior binding-site knowledge, we analysed binding trajectories to compare alternative binding pathways. Message-first binding is most frequently sampled but rarely reaches native-like structures (5.0%). In contrast, address-first binding occurs less often yet shows a 3.8-fold higher success rate (18.8%, p < 0.001). These results refine the message–address model and suggest that early address-domain engagement promotes productive μOR binding.
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ABSTRACT Understanding β-endorphin binding to the μ-opioid receptor (μOR) is crucial for designing safer analgesics. The peptide comprises a message domain mediating activation and an address domain conferring selectivity. Using 1,000 independent CABS-dock simulations, without prior binding-site knowledge, we analysed binding trajectories to compare alternative binding pathways. Message-first binding is most frequently sampled but rarely reaches native-like structures (5.0%). In contrast, address-first binding occurs less often yet shows a 3.8-fold higher success rate (18.8%, p < 0.001). These results refine the message–address model and suggest that early address-domain engagement promotes productive μOR binding. Competing Interest Statement The authors have declared no competing interest. Footnotes ABBREVIATIONS - OR - opioid receptor - GPCR - G-protein coupled receptor - PDB - protein data bank - RMSD - root-mean-squared deviation - μOR - μ-opioid receptor

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last seen: 2026-05-20T01:45:00.602351+00:00