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Structural Determinants for the Binding of Morphinan Agonists to the μ-Opioid Receptor.

Cong X, Campomanes P, Kless A, Schapitz I, Wagener M, Koch T, Carloni P - PLoS ONE (2015)

Bottom Line: Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations.Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor's activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond.This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Computational Biophysics, German Research School for Simulation Sciences GmbH, Joint venture of RWTH Aachen University and Forschungszentrum Jülich, 52425 Jülich, Germany; Computational Biomedicine section (IAS-5), Institute of Advanced Simulation (IAS), Forschungszentrum Jülich, 52425 Jülich, Germany; Computational Biomedicine section (INM-9), Institute of Neuroscience and Medicine (INM), Forschungszentrum Jülich, 52425 Jülich, Germany.

ABSTRACT
Atomistic descriptions of the μ-opioid receptor (μOR) noncovalently binding with two of its prototypical morphinan agonists, morphine (MOP) and hydromorphone (HMP), are investigated using molecular dynamics (MD) simulations. Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations. Alchemical free energy perturbation calculations show qualitative agreement with in vitro experiments performed in this work: indeed, the binding free energy difference between MOP and HMP computed by forward and backward alchemical transformation is 1.2±1.1 and 0.8±0.8 kcal/mol, respectively, to be compared with 0.4±0.3 kcal/mol from experiment. Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor's activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond. This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.

No MeSH data available.


Related in: MedlinePlus

Conformational change of μOR EL3 observed in the case of MOP binding.E310 in EL3 forms a salt-bridge with K233 (magenta dashed lines), which remains until the end of the simulation.
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pone.0135998.g005: Conformational change of μOR EL3 observed in the case of MOP binding.E310 in EL3 forms a salt-bridge with K233 (magenta dashed lines), which remains until the end of the simulation.

Mentions: In addition, our MD simulations show the impact of agonist binding on the flexibility of the extracellular loop 3 (EL3). MOP binding is associated with conformational changes in this loop (Fig 5). Notably, the presence of MOP in the active site pocket causes W318 side chain to move away from the ligand after 470 ns, which allows E310 in EL3 to form salt-bridge interactions with K233 that reduces EL3 mobility (Fig 5).


Structural Determinants for the Binding of Morphinan Agonists to the μ-Opioid Receptor.

Cong X, Campomanes P, Kless A, Schapitz I, Wagener M, Koch T, Carloni P - PLoS ONE (2015)

Conformational change of μOR EL3 observed in the case of MOP binding.E310 in EL3 forms a salt-bridge with K233 (magenta dashed lines), which remains until the end of the simulation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4539194&req=5

pone.0135998.g005: Conformational change of μOR EL3 observed in the case of MOP binding.E310 in EL3 forms a salt-bridge with K233 (magenta dashed lines), which remains until the end of the simulation.
Mentions: In addition, our MD simulations show the impact of agonist binding on the flexibility of the extracellular loop 3 (EL3). MOP binding is associated with conformational changes in this loop (Fig 5). Notably, the presence of MOP in the active site pocket causes W318 side chain to move away from the ligand after 470 ns, which allows E310 in EL3 to form salt-bridge interactions with K233 that reduces EL3 mobility (Fig 5).

Bottom Line: Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations.Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor's activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond.This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Computational Biophysics, German Research School for Simulation Sciences GmbH, Joint venture of RWTH Aachen University and Forschungszentrum Jülich, 52425 Jülich, Germany; Computational Biomedicine section (IAS-5), Institute of Advanced Simulation (IAS), Forschungszentrum Jülich, 52425 Jülich, Germany; Computational Biomedicine section (INM-9), Institute of Neuroscience and Medicine (INM), Forschungszentrum Jülich, 52425 Jülich, Germany.

ABSTRACT
Atomistic descriptions of the μ-opioid receptor (μOR) noncovalently binding with two of its prototypical morphinan agonists, morphine (MOP) and hydromorphone (HMP), are investigated using molecular dynamics (MD) simulations. Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations. Alchemical free energy perturbation calculations show qualitative agreement with in vitro experiments performed in this work: indeed, the binding free energy difference between MOP and HMP computed by forward and backward alchemical transformation is 1.2±1.1 and 0.8±0.8 kcal/mol, respectively, to be compared with 0.4±0.3 kcal/mol from experiment. Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor's activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond. This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.

No MeSH data available.


Related in: MedlinePlus