Limits...
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

Schematic model of the agonist-induced μOR conformational change into an active-like state.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4539194&req=5

pone.0135998.g007: Schematic model of the agonist-induced μOR conformational change into an active-like state.

Mentions: Comparison of the structural determinants at the active site suggests that H297 at TM6 plays an important role in the agonist-induced shift of TM6. H297 forms direct or water-mediated H-bonds as well as van der Waals interactions with the two agonists, consistent with its role as an “anchor” for opioids binding to μOR [50]. However, the agonists stabilize the residue in a position that is rather shifted relative to that in the β-FNA-μOR complex (Fig 6). Hence, we suggest that the ligand-H297 interaction is a key factor for the displacement of TM6 relative to TM3 (Fig 7).


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)

Schematic model of the agonist-induced μOR conformational change into an active-like state.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0135998.g007: Schematic model of the agonist-induced μOR conformational change into an active-like state.
Mentions: Comparison of the structural determinants at the active site suggests that H297 at TM6 plays an important role in the agonist-induced shift of TM6. H297 forms direct or water-mediated H-bonds as well as van der Waals interactions with the two agonists, consistent with its role as an “anchor” for opioids binding to μOR [50]. However, the agonists stabilize the residue in a position that is rather shifted relative to that in the β-FNA-μOR complex (Fig 6). Hence, we suggest that the ligand-H297 interaction is a key factor for the displacement of TM6 relative to TM3 (Fig 7).

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