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dc.contributor.authorMahinthichaichan, Paween
dc.contributor.authorVo, Quynh N
dc.contributor.authorEllis, Christopher R
dc.contributor.authorShen, Jana
dc.date.accessioned2022-01-19T16:38:37Z
dc.date.available2022-01-19T16:38:37Z
dc.date.issued2021-11-05
dc.identifier.urihttp://hdl.handle.net/10713/17623
dc.description.abstractDriven by illicit fentanyl, opioid related deaths have reached the highest level in 2020. Currently, an opioid overdose is resuscitated by the use of naloxone, which competitively binds and antagonizes the μ-opioid receptor (mOR). Thus, knowledge of the residence times of opioids at mOR and the unbinding mechanisms is valuable for assessing the effectiveness of naloxone. In the present study, we calculate the fentanyl-mOR dissociation time and elucidate the mechanism by applying an enhanced sampling molecular dynamics (MD) technique. Two sets of metadynamics simulations with different initial structures were performed while accounting for the protonation state of the conserved H2976.52, which has been suggested to modulate the ligand-mOR affinity and binding mode. Surprisingly, with the Nδ-protonated H2976.52, fentanyl can descend as much as 10 Å below the level of the conserved D1473.32 before escaping the receptor and has a calculated residence time τ of 38 s. In contrast, with the Nϵ- and doubly protonated H2976.52, the calculated τ are 2.6 and 0.9 s, respectively. Analysis suggests that formation of the piperidine-Hid297 hydrogen bond strengthens the hydrophobic contacts with the transmembrane helix (TM) 6, allowing fentanyl to explore a deep pocket. Considering the experimental τ of ∼4 min for fentanyl and the role of TM6 in mOR activation, the deep insertion mechanism may be biologically relevant. The work paves the way for large-scale computational predictions of opioid dissociation rates to inform evaluation of strategies for opioid overdose reversal. The profound role of the histidine protonation state found here may shift the paradigm in computational studies of ligand-receptor kinetics.en_US
dc.description.urihttps://doi.org/10.1021/jacsau.1c00341en_US
dc.language.isoenen_US
dc.publisherAmerican Chemical Society,en_US
dc.relation.ispartofJACS Auen_US
dc.rights© 2021 The Authors. Published by American Chemical Society.en_US
dc.titleKinetics and Mechanism of Fentanyl Dissociation from the μ-Opioid Receptor.en_US
dc.typeArticleen_US
dc.identifier.doi10.1021/jacsau.1c00341
dc.identifier.pmid34977892
dc.source.journaltitleJACS Au
dc.source.volume1
dc.source.issue12
dc.source.beginpage2208
dc.source.endpage2215
dc.source.countryUnited States


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