Skip to main content
SpringerLink
Log in

Cannabinoid CB1 receptor recognition of endocannabinoids via the lipid bilayer: molecular dynamics simulations of CB1 transmembrane helix 6 and anandamide in a phospholipid bilayer

  • Original Paper
  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

The phospholipid bilayer plays a central role in the lifecycle of the endogenous cannabinoid, N-arachidonoylethanolamine (anandamide, AEA). Therefore, the orientation and location of AEA in the phospholipid bilayer with respect to key membrane associated proteins, is a central issue in understanding the mechanism of endocannabinoid signaling. In this paper, we report a test of the hypothesis that a βXXβ motif (formed by beta branching amino acids, V6.43 and I6.46) on the lipid face of the cannabinoid CB1 receptor in its inactive state may serve as an initial CB1 interaction site for AEA. Eight 6 ns NAMD2 molecular dynamics simulations of AEA were conducted in a model system composed of CB1 transmembrane helix 6 (TMH6) in a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer. In addition, eight 6 ns NAMD2 molecular dynamics simulations of a low CB1 affinity (20:2, n−6) analog of AEA were conducted in the same model system. AEA was found to exhibit a higher incidence of V6.43/I6.46 groove insertion than did the (20:2, n−6) analog. In certain cases, AEA established a high energy of interaction with TMH6 by first associating with the V6.43/I6.46 groove and then molding itself to the lipid face of TMH6 to establish a hydrogen bonding interaction with the exposed backbone carbonyl of P6.50. Based upon these results, we propose that the formation of this hydrogen bonded AEA/TMH6 complex may be the initial step in CB1 recognition of AEA in the lipid bilayer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AEA:

N-arachidonoylethanolamine

CB1:

Cannabinoid Receptor Type 1

CM:

Conformational Memories

FAAH:

fatty acid amide hydrolase

GPCR:

G protein-coupled receptor

Rho:

Rhodopsin

References

  1. Di Marzo V, Melck D, Bisogno T, De Petrocellis L (1998) Trends Neurosci 21:521

  2. Piomelli D, Beltramo M, Giuffrida A, Stella N (1998) Neurobiol Dis 5:462

    Article  CAS  Google Scholar 

  3. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Science 258:1946

    Article  CAS  Google Scholar 

  4. McFarland MJ, Porter AC, Rakhshan FR, Rawat DS, Gibbs RA, Barker EL (2004) J Biol Chem 279:41991

    Article  CAS  Google Scholar 

  5. Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (2002) Science 298:1793

    Article  CAS  Google Scholar 

  6. Gerard CM, Mollereau C, Vassart G, Parmentier M (1991) Biochem J 279(Pt 1):129

    CAS  Google Scholar 

  7. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR et al (1995) Biochem Pharmacol 50:83

    Article  CAS  Google Scholar 

  8. Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R (2001) Proc Natl Acad Sci USA 98:3662

    Article  CAS  Google Scholar 

  9. Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao J, Nomikos GG, Carter P, Bymaster FP, Leese AB, Felder CC (2002) J Pharmacol Exp Ther 301:1020

    Article  CAS  Google Scholar 

  10. Reggio PH (2005) Handb Exp Pharmacol 247

  11. Thakur GA, Duclos RI Jr, Makriyannis A (2005) Life Sci 78:454

    Article  CAS  Google Scholar 

  12. Mahadevan A, Razdan RK (2005) Aaps J 7:E496

    Article  CAS  Google Scholar 

  13. Sheskin T, Hanus L, Slager J, Vogel Z, Mechoulam R (1997) J Med Chem 40:659

    Article  CAS  Google Scholar 

  14. Reggio PH, Traore H (2000) Chem Phys Lipids 108:15

    Article  CAS  Google Scholar 

  15. Palmer SL, Khanolkar AD, Makriyannis A (2000) Curr Pharm Des 6:1381

    Article  CAS  Google Scholar 

  16. Pinto JC, Potie F, Rice KC, Boring D, Johnson MR, Evans DM, Wilken GH, Cantrell CH, Howlett AC (1994) Mol Pharmacol 46:516

    CAS  Google Scholar 

  17. Berglund BA, Boring DL, Howlett AC (1999) Adv Exp Med Biol 469:527

    CAS  Google Scholar 

  18. Berglund BA, Fleming PR, Rice KC, Shim JY, Welsh WJ, Howlett AC (2000) Drug Des Discov 16:281

    CAS  Google Scholar 

  19. Barnett-Norris J, Hurst DP, Buehner K, Ballesteros JA, Guarnieri F, Reggio PH (2002) Int J Quantum Chem 88:76

    Article  CAS  Google Scholar 

  20. Reggio PH, Nebane NM, Lynch DL, Song Z-H (2005) In: Musty R (ed) 2005 Symposium on the Cannabinoids, vol 15. ICRS, Clearwater, Florida, p 21

  21. Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HH, George SR, O’Dowd BF (1999) Brain Res Mol Brain Res 64:193

    Article  CAS  Google Scholar 

  22. Drmota T, Greasley P, Groblewski T (2004). Astrazeneca, USA

  23. O’Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, Kolakowski LF Jr, George SR (1998) Genomics 47:310

    Article  CAS  Google Scholar 

  24. Kale L, Skeel R, Bhandaarkar M, Brunner R, Gursoy A, Krawetz N, Phillips J, Shinozaki A, Varadarajan K, Schulten K (1999) J Comp Phys 151:283

    Article  CAS  Google Scholar 

  25. Schlenkrich M, Brickmann J, MacKerell AD, Jr., Karplus M (1996) In: Merz KM, Roux B (eds) Biological membranes: a molecular perspective from computation and experiment. Birkhauser, Boston, MA, p 31

  26. MacKerell AD Jr, Bashford D, Bellot M, Dunbrack RL Jr, Evanseck J, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph D, Kuchnir L, Kuczera K, Lau FT K, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher IWE, Roux B, Schlenkrich M, Smith J, Stote R, Straub J, Watanabe M, Wiorkiewicz-Kuczera J, Yin D, Karplus M (1998) J Phys Chem B 102:3586

    Article  CAS  Google Scholar 

  27. Feller SE, MacKerell AD Jr (2000) J Phys Chem B 104:7510

    Article  CAS  Google Scholar 

  28. Feller SE, Gawrisch K, MacKerell AD Jr (2002) J Am Chem Soc 124:318

    Article  CAS  Google Scholar 

  29. Darden TA, York D, Pedersen L (1993) J Chem Phys 98:10089

    Article  CAS  Google Scholar 

  30. Lynch DL, Reggio PH (2005) J Med Chem 48:4824

    Article  CAS  Google Scholar 

  31. Bhandarkar M, Brunner R, Chipot C, Dalke A, Dixit A, Grayson P, Gullingsrud J, Gursoy A, Hardy D, Humphrey W, Hurwitz D, Krawetz N, Nelson M, Phillips J, Shinozaki A, Zheng G, Zhu F (2006) NAMD2 User’s Guide, Version 2.6, http://www.ks.uiuc.edu/Research/namd/2.6/ug

  32. Humphrey W, Dalke A, Schulten K (1996) J Mol Graph 14:33

    Article  CAS  Google Scholar 

  33. Elmore DE, Dougherty DA (2003) Biophys J 85:1512

    CAS  Google Scholar 

  34. Ballesteros JA, Weinstein H (1995) In: Sealfon SC (ed) Methods in neuroscience, vol 25. Academic Press, San Diego, CA, p 366

  35. Saiz L, Klein ML (2001) Biophys J 81:204

    CAS  Google Scholar 

  36. Chiu SW, Jakobsson E, Subramaniam S, Scott HL (1999) Biophys J 77:2462

    CAS  Google Scholar 

  37. Xu Z, Bernlohr DA, Banaszak LJ (1992) Biochemistry 31:3484

    Article  CAS  Google Scholar 

  38. Xu Z, Bernlohr DA, Banaszak LJ (1993) J Biol Chem 268:7874

    CAS  Google Scholar 

  39. Patricelli MP, Cravatt BF (2001) Biochemistry 40:6107

    Article  CAS  Google Scholar 

  40. Mirzadegan T, Benko G, Filipek S, Palczewski K (2003) Biochemistry 42:2759

    Article  CAS  Google Scholar 

  41. Ballesteros JA, Deupi X, Olivella M, Haaksma EE, Pardo L (2000) Biophys J 79:2754

    Article  CAS  Google Scholar 

  42. Skorkowska K, Adamiec R (2005) Int Angiol 24:215

    CAS  Google Scholar 

  43. Day JR, Punjabi PP, Randi AM, Haskard DO, Landis RC, Taylor KM (2004) Circulation 110:2597

    Article  CAS  Google Scholar 

  44. Sugiura T, Kodaka T, Nakane S, Kishimoto S, Kondo S, Waku K (1998) Biochem Biophys Res Commun 243:838

    Article  CAS  Google Scholar 

  45. Coetzee C, Levendal RA, van de Venter M, Frost CL (2006) Phytomedicine, April 25, Epub

  46. Smith GD, Jaffe RL (1996) J Phys Chem 100:18718

    Article  CAS  Google Scholar 

  47. Rabinovich AL, Ripatti PO (1991) Biochim Biophys Acta 1085:53

    CAS  Google Scholar 

  48. Rich MR (1993) Biochim Biophys Acta 1178:87

    Article  CAS  Google Scholar 

  49. Barnett-Norris J, Hurst DP, Lynch DL, Guarnieri F, Makriyannis A, Reggio PH (2002) J Med Chem 45:3649

    Article  CAS  Google Scholar 

  50. Sarramegn V, Muller I, Milon A, Talmont F (2006) Cell Mol Life Sci 63:1149

    Article  CAS  Google Scholar 

  51. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Science 289:739

    Article  CAS  Google Scholar 

  52. Okada T, Fujiyoshi Y, Silow M, Navarro J, Landau EM, Shichida Y (2002) Proc Natl Acad Sci USA 99:5982

    Article  CAS  Google Scholar 

  53. Li J, Edwards PC, Burghammer M, Villa C, Schertler GF (2004) J Mol Biol 343:1409

    Article  CAS  Google Scholar 

  54. Schertler GF (2005) Curr Opin Struct Biol 15:408

    Article  CAS  Google Scholar 

  55. Szundi I, Ruprecht JJ, Epps J, Villa C, Swartz TE, Lewis JW, Schertler GF, Kliger DS (2006) Biochemistry 45:4974

    Article  CAS  Google Scholar 

  56. Farrens D, Altenbach C, Ynag K, Hubbell W, Khorana H (1996) Science 274:768

    Article  CAS  Google Scholar 

  57. Ghanouni P, Steenhuis JJ, Farrens DL, Kobilka BK (2001) Proc Natl Acad Sci USA 98:5997

    Article  CAS  Google Scholar 

  58. Lin SW, Sakmar TP (1996) Biochemistry 35:11149

    Article  CAS  Google Scholar 

  59. Javitch JA, Fu D, Liapakis G, Chen J (1997) J Biol Chem 272:18546

    Article  CAS  Google Scholar 

  60. Jensen AD, Guarnieri F, Rasmussen SG, Asmar F, Ballesteros JA, Gether U (2001) J Biol Chem 276:9279

    Article  CAS  Google Scholar 

  61. Nakanishi J, Takarada T, Yunoki S, Kikuchi Y, Maeda M (2006) Biochem Biophys Res Commun 343:1191

    Article  CAS  Google Scholar 

  62. Ward SD, Hamdan FF, Bloodworth LM, Siddiqui NA, Li JH, Wess J (2006) Biochemistry 45:676

    Article  CAS  Google Scholar 

  63. McAllister SD, Hurst DP, Barnett-Norris J, Lynch D, Reggio PH, Abood ME (2004) J Biol Chem 279:48024

    Article  CAS  Google Scholar 

  64. Barnett-Norris J, Guarnieri F, Hurst DP, Reggio PH (1998) J Med Chem 41:4861

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIDA grants DA03934 and DA000489 (PHR) and supercomputing support was provided by the Pittsburgh Supercomputer Center, AAB grant numbers MCB030006P and MCB030017. This work was also supported by the Theoretical and Computational Biophysics group, an NIH Resource for Macromolecular Modeling and Bioinformatics, at the Beckman Institute, University of Illinois at Urbana–Champaign, through the use of the software packages NAMD2 and VMD (Figs. 4 and 5 were prepared using VMD). The authors wish to thank Dow Hurst and Judy Barnett-Norris for their technical assistance in the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Center for Drug Design, Department of Chemistry and Biochemistry, University of North Carolina Greensboro, 435 New Science Building, P.O. Box 26170, Greensboro, NC, 27402-6170, USA

    Diane L. Lynch & Patricia H. Reggio

Authors
  1. Diane L. Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patricia H. Reggio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patricia H. Reggio.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lynch, D.L., Reggio, P.H. Cannabinoid CB1 receptor recognition of endocannabinoids via the lipid bilayer: molecular dynamics simulations of CB1 transmembrane helix 6 and anandamide in a phospholipid bilayer. J Comput Aided Mol Des 20, 495–509 (2006). https://doi.org/10.1007/s10822-006-9068-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-006-9068-9

Keywords

Search

Navigation