Mechanistic basis of μ-opioid receptor allosteric modulation from molecular simulations
- 1Chemistry Department, Pomona College, 645 N College Ave, Claremont, CA, 91711
- 2Beckman Institute, California Institute of Technology, 1200 E. California Blvd., Pasadena, CA, United States, 91125
Abstract
The μ-opioid receptor (μOR) is a central mediator of analgesia and opioid-induced adverse effects, yet the molecular basis by which allosteric modulators reshape receptor signaling remains poorly understood. Here, we integrate all-atom molecular dynamics with unbinding kinetics simulations to resolve the mechanistic basis of positive and negative allosteric modulation of μOR. We show that the positive allosteric modulator BMS-986122 enhances signaling not through uniform stabilization of canonical active microswitches, but by selectively remodeling the sodium pocket and, critically, stabilizing the μOR–G protein interface. This stabilization increases interfacial interactions and buried surface area, providing a G protein–dependent mechanism for enhanced efficacy despite increased agonist conformational flexibility and weakened orthosteric contacts. In contrast, the negative allosteric modulator compound 368 broadly enforces inactive-like microswitch conformations while simultaneously stabilizing antagonist binding. Unbinding kinetics simulations reveal that 368 exerts a dominant kinetic effect, restricting naloxone egress pathways and increasing residence time by approximately three orders of magnitude. Together, these results establish a unified framework in which μOR allostery operates through modulation of receptor and ligand conformational dynamics, G protein engagement, and ligand dissociation kinetics. This work provides an atomistic foundation for the rational design of next-generation opioid therapeutics that exploit allosteric mechanisms to enhance efficacy and safety.
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BibTeX
@misc{kwak2026mechanistic,
title = {{Mechanistic basis of μ-opioid receptor allosteric modulation from molecular simulations}},
author = {Liam Kwak and Roberto Garza-López},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010296/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010296/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Mechanistic basis of μ-opioid receptor allosteric modulation from molecular simulations
AU - Liam Kwak
AU - Roberto Garza-López
PY - 2026
DA - 2026/10/12
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010296/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010296/v1
AB - The μ-opioid receptor (μOR) is a central mediator of analgesia and opioid-induced adverse effects, yet the molecular basis by which allosteric modulators reshape receptor signaling remains poorly understood. Here, we integrate all-atom molecular dynamics with unbinding kinetics simulations to resolve the mechanistic basis of positive and negative allosteric modulation of μOR. We show that the positive allosteric modulator BMS-986122 enhances signaling not through uniform stabilization of canonical active microswitches, but by selectively remodeling the sodium pocket and, critically, stabilizing the μOR–G protein interface. This stabilization increases interfacial interactions and buried surface area, providing a G protein–dependent mechanism for enhanced efficacy despite increased agonist conformational flexibility and weakened orthosteric contacts. In contrast, the negative allosteric modulator compound 368 broadly enforces inactive-like microswitch conformations while simultaneously stabilizing antagonist binding. Unbinding kinetics simulations reveal that 368 exerts a dominant kinetic effect, restricting naloxone egress pathways and increasing residence time by approximately three orders of magnitude. Together, these results establish a unified framework in which μOR allostery operates through modulation of receptor and ligand conformational dynamics, G protein engagement, and ligand dissociation kinetics. This work provides an atomistic foundation for the rational design of next-generation opioid therapeutics that exploit allosteric mechanisms to enhance efficacy and safety.
ER -