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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

The thermodynamic cycle for computing the free energy difference between MOP and HMP upon binding to μOR: The unbound state requires transformation of the ligands alone in solution, since the receptor is the same in both cases.
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pone.0135998.g002: The thermodynamic cycle for computing the free energy difference between MOP and HMP upon binding to μOR: The unbound state requires transformation of the ligands alone in solution, since the receptor is the same in both cases.

Mentions: Alchemical free energy perturbation (FEP) methodologies were employed to estimate the difference in the binding free energy to μOR, ∆∆Gbind, between MOP and HMP. Using the thermodynamic cycle in Fig 2, ∆∆Gbind from MOP to HMP can be calculated as the free energy difference between two alchemical pathways: the transformation of MOP to HMP while bound to μOR, and that of MOP to HMP in solution (unbound). We performed alchemical transformation from MOP to HMP and vice versa.


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)

The thermodynamic cycle for computing the free energy difference between MOP and HMP upon binding to μOR: The unbound state requires transformation of the ligands alone in solution, since the receptor is the same in both cases.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0135998.g002: The thermodynamic cycle for computing the free energy difference between MOP and HMP upon binding to μOR: The unbound state requires transformation of the ligands alone in solution, since the receptor is the same in both cases.
Mentions: Alchemical free energy perturbation (FEP) methodologies were employed to estimate the difference in the binding free energy to μOR, ∆∆Gbind, between MOP and HMP. Using the thermodynamic cycle in Fig 2, ∆∆Gbind from MOP to HMP can be calculated as the free energy difference between two alchemical pathways: the transformation of MOP to HMP while bound to μOR, and that of MOP to HMP in solution (unbound). We performed alchemical transformation from MOP to HMP and vice versa.

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