scholarly journals Fentanyl binds to the μ-opioid receptor via the lipid membrane and transmembrane helices

2021 ◽  
Author(s):  
Katy J Sutcliffe ◽  
Robin A Corey ◽  
Steven J Charlton ◽  
Richard B Sessions ◽  
Graeme Henderson ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Lipid Membrane ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Transmembrane Helices ◽  
Opioid Agonist ◽  
The Usa ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations

AbstractOverdose deaths from synthetic opioids, such as fentanyl, have reached epidemic proportions in the USA and are increasing worldwide. Fentanyl is a potent opioid agonist, that is less well reversed by naloxone than morphine. Due to fentanyl’s high lipophilicity and elongated structure we hypothesised that its unusual pharmacology may be explained by a novel binding mode to the μ-opioid receptor (MOPr).By employing coarse-grained molecular dynamics simulations and free energy calculations, we determined the routes by which fentanyl and morphine access the orthosteric pocket of MOPr.Morphine accesses MOPr via the aqueous pathway; first binding to an extracellular vestibule, then diffusing into the orthosteric pocket. In contrast, fentanyl takes a novel route; first partitioning into the membrane, before accessing the orthosteric site by diffusing through a ligand-induced gap between the transmembrane helices.This novel lipophilic route may explain the high potency and lower susceptibility of fentanyl to reversal by naloxone.

scholarly journals Dispersion state phase diagram of citrate-coated metallic nanoparticles in saline solutions

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sebastian Franco-Ulloa ◽  
Giuseppina Tatulli ◽  
Sigbjørn Løland Bore ◽  
Mauro Moglianetti ◽  
Pier Paolo Pompa ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ionic Strength ◽  
Molecular Dynamics Simulations ◽  
Metal Nanoparticles ◽  
Metallic Nanoparticles ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Solvent Accessible Surface Area ◽  
Dispersion State ◽  
Dynamics Simulations

Abstract The fundamental interactions underlying citrate-mediated chemical stability of metal nanoparticles, and their surface characteristics dictating particle dispersion/aggregation in aqueous solutions, are largely unclear. Here, we developed a theoretical model to estimate the stoichiometry of small, charged ligands (like citrate) chemisorbed onto spherical metallic nanoparticles and coupled it with atomistic molecular dynamics simulations to define the uncovered solvent-accessible surface area of the nanoparticle. Then, we integrated coarse-grained molecular dynamics simulations and two-body free energy calculations to define dispersion state phase diagrams for charged metal nanoparticles in a range of medium’s ionic strength, a known trigger for aggregation. Ultraviolet-visible spectroscopy experiments of citrate-capped nanocolloids validated our predictions and extended our results to nanoparticles up to 35 nm. Altogether, our results disclose a complex interplay between the particle size, its surface charge density, and the ionic strength of the medium, which ultimately clarifies how these variables impact colloidal stability.

Inflammation-reactive astrocytes can be restored with a three drug combination

2014 ◽  
Vol 5 (3) ◽  
pp. 209-209
Author(s):  
E. Hansson ◽  
L. Block ◽  
U. Björklund ◽  
B. Biber
Keyword(s):  
Opioid Receptor ◽  
Primary Cultures ◽  
Reactive Astrocytes ◽  
Opioid Antagonist ◽  
Opioid Agonist ◽  
Cell Parameters ◽  
Ultralow Concentrations ◽  
Inflammatory State ◽  
Μ Opioid Receptor

Abstract Aims In inflammation-reactive astrocytes the cell parameters, Ca2+ signalling, Na+ transporters, cytoskeleton, and release of proinflammatory cytokines are affected. We want to re-establish these parameters with agents, which might have a potential to restore the cells back to a normal non-inflammatory level. Methods Astrocytes in primary cultures were incubated with lipopolysaccharide (LPS) (10 ng/ml) for 24 h to become inflammation-reactive. Different parameters were analysed to verify this inflammation: Ca2+ signalling, Na+/K+-ATPase expression, actin filament organization, and interleukin-1beta release (IL-1β). Results We have used an opioid agonist, endomorphin-1, that stimulates the Gi/o protein of the μ-opioid receptor, an opioid antagonist, naloxone, that inhibits the Gs protein of the μ-opioid receptor in ultralow concentrations, and an anti-epileptic agent, levetiracetam, that counteracts the release of IL-1β. The combination of these three agents managed to activate the Gi/o protein and Na+/K+-ATPase activity, inhibit the Gs protein, and decrease the release of IL-1β. The disorganized actin filaments were restored. Conclusions The findings that the important cell parameters in astrocytes were restored back to their normal non-inflammatory state after the cells were treated with the inflammatory agent LPS could be of clinical significance. It may be useful for the treatment of neuroinflammation and also maybe of long-term pain. The astrocyte networks play a significant role and therefore a well-working intercellular Ca2+ signalling is of utmost importance. Significance These findings put new potential drug regimens towards treatment of neuroinflammation and long-term pain into focus.

A Finite Element-Based Coarse-Grained Model for Cell–Nanomaterial Interactions by Combining Absolute Nodal Coordinate Formula and Brownian Dynamics

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Teng Ma ◽  
Yuanpeng Liu ◽  
Guochang Lin ◽  
Changguo Wang ◽  
Huifeng Tan
Keyword(s):  
Finite Element ◽  
Brownian Dynamics ◽  
Lipid Membrane ◽  
Contact Region ◽  
Detection Algorithm ◽  
Polymer Chains ◽  
Coarse Grained ◽  
Absolute Nodal Coordinate ◽  
Coarse Grained Model ◽  
Dynamics Simulations

Abstract A fundamental understanding of the interactions between one-dimensional nanomaterials and the cell membrane is of great importance for assessing the hazardous effects of viruses and improving the performance of drug delivery. Here, we propose a finite element-based coarse-grained model to describe the cell entry of nanomaterials based on an absolute nodal coordinate formula and Brownian dynamics. The interactions between nanoparticles and lipid membrane are described by the Lennard–Jones potential, and a contact detection algorithm is used to determine the contact region. Compared with the theoretical and published experimental results, the correctness of the model has been verified. We take two examples to test the robustness of the model: the endocytosis of nanorods grafted with polymer chains and simultaneous entry of multiple nanorods into a lipid membrane. It shows that the model can not only capture the effect of ligand–receptor binding on the penetration but also accurately characterize the cooperative or separate entry of multiple nanorods. This coarse-grained model is computationally highly efficient and will be powerful in combination with molecular dynamics simulations to provide an understanding of cell–nanomaterial interactions.

scholarly journals Molecular stripping in theNF-κB/IκB/DNAgenetic regulatory network

2015 ◽  
Vol 113 (1) ◽  
pp. 110-115 ◽  
Author(s):  
Davit A. Potoyan ◽  
Weihua Zheng ◽  
Elizabeth A. Komives ◽  
Peter G. Wolynes
Keyword(s):  
Free Energy ◽  
Transcription Factor ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Genetic Switch ◽  
Binary And Ternary Complexes ◽  
Landscape Models ◽  
Gene Switches ◽  
Dna Release ◽  
Dynamics Simulations

Genetic switches based on theNF-κB/IκB/DNAsystem are master regulators of an array of cellular responses. Recent kinetic experiments have shown thatIκBcan actively removeNF-κBbound to its genetic sites via a process called “molecular stripping.” This allows theNF-κB/IκB/DNAswitch to function under kinetic control rather than the thermodynamic control contemplated in the traditional models of gene switches. Using molecular dynamics simulations of coarse-grained predictive energy landscape models for the constituent proteins by themselves and interacting with the DNA we explore the functional motions of the transcription factorNF-κBand its various binary and ternary complexes with DNA and the inhibitorIκB. These studies show that the function of theNF-κB/IκB/DNAgenetic switch is realized via an allosteric mechanism. Molecular stripping occurs through the activation of a domain twist mode by the binding ofIκBthat occurs through conformational selection. Free energy calculations for DNA binding show that the binding ofIκBnot only results in a significant decrease of the affinity of the transcription factor for the DNA but also kinetically speeds DNA release. Projections of the free energy onto various reaction coordinates reveal the structural details of the stripping pathways.

μ-Opioid receptor agonist effects on medullary respiratory neurons in the cat: evidence for involvement in certain types of ventilatory disturbances

2003 ◽  
Vol 285 (6) ◽  
pp. R1287-R1304 ◽  
Author(s):  
Peter M. Lalley
Keyword(s):  
Tidal Volume ◽  
Chest Wall ◽  
Opioid Receptor ◽  
Membrane Properties ◽  
Respiratory Neurons ◽  
Opioid Agonist ◽  
Chest Wall Compliance ◽  
Wall Compliance ◽  
Μ Opioid Receptor ◽  
Synaptic Drive

μ-Opioid receptor agonists depress tidal volume, decrease chest wall compliance, and increase upper airway resistance. In this study, potential neuronal sites and mechanisms responsible for the disturbances were investigated, dose-response relationships were established, and it was determined whether general anesthesia plays a role. Effects of μ-opioid agonists on membrane properties and discharges of respiratory bulbospinal, vagal, and propriobulbar neurons and phrenic nerve activity were measured in pentobarbital-anesthetized and unanesthetized decerebrate cats. In all types of respiratory neurons tested, threshold intravenous doses of the μ-opioid agonist fentanyl slowed discharge frequency and prolonged duration without altering peak discharge intensity. Larger doses postsynaptically depressed discharges of inspiratory bulbospinal and inspiratory propriobulbar neurons that might account for depression of tidal volume. Iontophoresis of the μ-opioid agonist DAMGO also depressed the intensity of inspiratory bulbospinal neuron discharges. Fentanyl given intravenously prolonged discharges leading to tonic firing of bulbospinal expiratory neurons in association with reduced hyperpolarizing synaptic drive potentials, perhaps explaining decreased inspiratory phase chest wall compliance. Lowest effective doses of fentanyl had similar effects on vagal postinspiratory (laryngeal adductor) motoneurons, whereas in vagal laryngeal abductor and pharyngeal constrictor motoneurons, depression of depolarizing synaptic drive potentials led to sparse, very-low-frequency discharges. Such effects on three types of vagal motoneurons might explain tonic vocal fold closure and pharyngeal obstruction of airflow. Measurements of membrane potential and input resistance suggest the effects on bulbospinal Aug-E neurons and vagal motoneurons are mediated presynaptically. Opioid effects on the respiratory neurons were similar in anesthetized and decerebrate preparations.

scholarly journals Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the μ-Opioid Receptor Upon Activation

2020 ◽  
Vol 21 (13) ◽  
pp. 4699 ◽  
Author(s):  
Zhennan Zhao ◽  
Tingting Huang ◽  
Jiazhong Li
Keyword(s):  
Molecular Dynamics ◽  
Side Effects ◽  
G Protein ◽  
Opioid Receptor ◽  
Conformational Changes ◽  
Opioid Analgesics ◽  
Dynamics Simulation ◽  
Analgesic Effects ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations

Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W2936.48 (Ballesteros–Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W3187.35, Y3267.43, and Y3367.53 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR–ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.

Multiscale design of coarse-grained elastic network-based potentials for the μ opioid receptor

2016 ◽  
Vol 22 (9) ◽  
Author(s):  
Mathieu Fossépré ◽  
Laurence Leherte ◽  
Aatto Laaksonen ◽  
Daniel P. Vercauteren
Keyword(s):  
Opioid Receptor ◽  
Coarse Grained ◽  
Elastic Network ◽  
Μ Opioid Receptor

Interaction of fullerene chains and a lipid membrane via computer simulations

RSC Advances ◽  
2014 ◽  
Vol 4 (57) ◽  
pp. 30215-30220 ◽  
Author(s):  
Wen-de Tian ◽  
Kang Chen ◽  
Yu-qiang Ma
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Computer Simulations ◽  
Membrane Structure ◽  
Lipid Membrane ◽  
Coarse Grained ◽  
Structure Dynamics ◽  
Dynamics Simulations ◽  
Fullerene Polymers ◽  
Coarse Grained Molecular Dynamics

Coarse-grained molecular dynamics simulations were employed to study the fullerene polymers with various functionalization degrees interacting with the DPPC membrane. Structure, dynamics, and thermodynamics of systems were analyzed.

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