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Journal of Molecular Modeling

, Volume 17, Issue 9, pp 2353–2366 | Cite as

Modeling of ligand binding to G protein coupled receptors: cannabinoid CB1, CB2 and adrenergic β2AR

  • Dorota Latek
  • Michal Kolinski
  • Umesh Ghoshdastider
  • Aleksander Debinski
  • Rafal Bombolewski
  • Anita Plazinska
  • Krzysztof Jozwiak
  • Slawomir Filipek
Original Paper

Abstract

Cannabinoid and adrenergic receptors belong to the class A (similar to rhodopsin) G protein coupled receptors. Docking of agonists and antagonists to CB1 and CB2 cannabinoid receptors revealed the importance of a centrally located rotamer toggle switch and its possible participation in the mechanism of agonist/antagonist recognition. The switch is composed of two residues, F3.36 and W6.48, located on opposite transmembrane helices TM3 and TM6 in the central part of the membranous domain of cannabinoid receptors. The CB1 and CB2 receptor models were constructed based on the adenosine A2A receptor template. The two best scored conformations of each receptor were used for the docking procedure. In all poses (ligand-receptor conformations) characterized by the lowest ligand-receptor intermolecular energy and free energy of binding the ligand type matched the state of the rotamer toggle switch: antagonists maintained an inactive state of the switch, whereas agonists changed it. In case of agonists of β2AR, the (R,R) and (S,S) stereoisomers of fenoterol, the molecular dynamics simulations provided evidence of different binding modes while preserving the same average position of ligands in the binding site. The (S,S) isomer was much more labile in the binding site and only one stable hydrogen bond was created. Such dynamical binding modes may also be valid for ligands of cannabinoid receptors because of the hydrophobic nature of their ligand-receptor interactions. However, only very long molecular dynamics simulations could verify the validity of such binding modes and how they affect the process of activation.

Figure

The rotamer toggle switch in cannabinoid receptors is comprised of two residues, F3.36 and W6.48, which are located on transmembrane helices TM3 and TM6. Docking of agonists and antagonists to CB1 and CB2 cannabinoid receptors revealed the importance of this centrally located switch and its possible participation in the mechanism of agonist/antagonist sensing. The best scored poses (ligand-receptor conformations) were obtained for the ligands matching the switch state: antagonists maintained the state of the rotamer toggle switch, whereas agonists changed it

Keywords

Cannabinoid receptors Docking Fenoterol GPCRs Molecular dynamics Molecular switches 

Notes

Acknowledgments

The work was supported by the Polish Ministry of Science and Higher Education (Grant no. N N301 2038 33) and by the Foundation for Polish Science (FOCUS and TEAM programmes). Publication supported by the European Union (Innovative Economy - European Regional Development Fund) grant no. POIG.02.03.00-00-003/09. We also acknowledge the computational grants no. G07-13 and G35-6 awarded by the Interdisciplinary Centre for Mathematical and Computational Modelling in Warsaw.

Supplementary material

894_2011_986_MOESM1_ESM.pdf (1.4 mb)
Figure S1 The alignment of human CB1 and CB2 receptor sequences with these of A2AR (a) and β1AR (b) templates. Transmembrane helices of templates are encircled (red dashed mline), the conserved residues (x.50) in each helix are in blue and cysteine residues forming disulfide bridge are in yellow. Conserved sequence motifs in cannabinoid receptors are underlined (PDF 1400 kb)
894_2011_986_MOESM2_ESM.pdf (355 kb)
Figure S2 The representative plots of χ 1 torsion angle for residues in the rotamer toggle switch (F3.36 and W6.48) for the best scored receptor models based on the A2AR template from Modeller. (a) and (b) CB1 receptor; (c) and (d) CB2 receptor. Molecular dynamics simulations were conducted using IMM1 method (employing implicit membrane) in CHARMM program. Frames were saved every 1 ps (PDF 355 kb)
894_2011_986_MOESM3_ESM.pdf (311 kb)
Figure S3 The RMSD plots of complexes of cannabinoid receptors during 5.5 ns MD simulations in explicit POPC membrane in YASARA program. Red line indicates plot for Cα atoms of transmembrane region; green line – plot for Cα atoms of residues from the binding site of the receptor. Frames were saved every 25 ps (PDF 310 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Dorota Latek
    • 1
    • 5
  • Michal Kolinski
    • 2
  • Umesh Ghoshdastider
    • 1
    • 3
  • Aleksander Debinski
    • 1
  • Rafal Bombolewski
    • 4
  • Anita Plazinska
    • 2
  • Krzysztof Jozwiak
    • 2
  • Slawomir Filipek
    • 1
  1. 1.Faculty of ChemistryUniversity of WarsawWarsawPoland
  2. 2.Department of ChemistryMedical University of LublinLublinPoland
  3. 3.Centre for Biomolecular Magnetic Resonance, Institute for Biophysical ChemistryGoethe-University of Frankfurt/MainFrankfurt/MainGermany
  4. 4.Faculty of PhysicsUniversity of WarsawWarsawPoland
  5. 5.International Institute of Molecular and Cell BiologyWarsawPoland

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