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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

Superimposition of representative MD structures obtained by cluster analysis (see Materials and Methods) for (A) MOP-μOR and (B) HMP-μOR onto the X-ray structure of β-FNA-μOR [18].Dashed lines indicate H-bonds.
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pone.0135998.g006: Superimposition of representative MD structures obtained by cluster analysis (see Materials and Methods) for (A) MOP-μOR and (B) HMP-μOR onto the X-ray structure of β-FNA-μOR [18].Dashed lines indicate H-bonds.

Mentions: Finally, we compare the two agonists with β-FNA. The three ligands feature very similar polycyclic ring skeletons and a common salt bridge with D147. However, β-FNA shows different H-bond pattern: two water molecules mediate the ligand’s H-bonds with H297 and K233, which are preserved throughout the two independent MD simulations. Such pattern is not retained in either of the two agonists (Fig 6). This is likely due to the covalent bond between β-FNA and K233, which constraints the antagonist’s location and mobility in the binding pocket.


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)

Superimposition of representative MD structures obtained by cluster analysis (see Materials and Methods) for (A) MOP-μOR and (B) HMP-μOR onto the X-ray structure of β-FNA-μOR [18].Dashed lines indicate H-bonds.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0135998.g006: Superimposition of representative MD structures obtained by cluster analysis (see Materials and Methods) for (A) MOP-μOR and (B) HMP-μOR onto the X-ray structure of β-FNA-μOR [18].Dashed lines indicate H-bonds.
Mentions: Finally, we compare the two agonists with β-FNA. The three ligands feature very similar polycyclic ring skeletons and a common salt bridge with D147. However, β-FNA shows different H-bond pattern: two water molecules mediate the ligand’s H-bonds with H297 and K233, which are preserved throughout the two independent MD simulations. Such pattern is not retained in either of the two agonists (Fig 6). This is likely due to the covalent bond between β-FNA and K233, which constraints the antagonist’s location and mobility in the binding pocket.

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