Journal of Computer-Aided Molecular Design

, Volume 20, Issue 7–8, pp 405–416

Dynamic models of G-protein coupled receptor dimers: indications of asymmetry in the rhodopsin dimer from molecular dynamics simulations in a POPC bilayer

Original Paper

Abstract

Based on the growing evidence that G-protein coupled receptors (GPCRs) form homo- and hetero-oligomers, models of GPCR signaling are now considering macromolecular assemblies rather than monomers, with the homo-dimer regarded as the minimal oligomeric arrangement required for functional coupling to the G-protein. The dynamic mechanisms of such signaling assemblies are unknown. To gain some insight into properties of GPCR dimers that may be relevant to functional mechanisms, we study their current structural prototype, rhodopsin. We have carried out nanosecond time-scale molecular dynamics (MD) simulations of a rhodopsin dimer and compared the results to the monomer simulated in the same type of bilayer membrane model composed of an equilibrated unit cell of hydrated palmitoyl-oleoyl-phosphatidyl choline (POPC). The dynamic representation of the homo-dimer reveals the location of structural changes in several regions of the monomeric subunits. These changes appear to be more pronounced at the dimerization interface that had been shown to be involved in the activation process [Proc Natl Acad Sci USA 102:17495, 2005]. The results are consistent with a model of GPCR activation that involves allosteric modulation through a single GPCR subunit per dimer.

Keywords

GPCRs Dimerization Allosteric mechanism Dynamic mechanisms Membrane bilayer Essential dynamics GROMACS 

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References

  1. 1.
    Terrillon S, Bouvier M (2004) EMBO Rep 5(1):30CrossRefGoogle Scholar
  2. 2.
    Javitch JA (2004) Mol Pharmacol 66(5):1077CrossRefGoogle Scholar
  3. 3.
    Milligan G (2004) Mol Pharmacol 66(1):1CrossRefGoogle Scholar
  4. 4.
    Bai M (2004) Cell Signal 16(2):175CrossRefGoogle Scholar
  5. 5.
    Park PS, Filipek S, Wells JW, Palczewski K (2004) Biochemistry 43(50):15643CrossRefGoogle Scholar
  6. 6.
    Filizola M, Weinstein H (2005) Curr Opin Drug Discov Devel 8(5):577Google Scholar
  7. 7.
    Fotiadis D, Jastrzebska B, Philippsen A, Muller DJ, Palczewski K, Engel A (2006) Curr Opin Struct Biol 16(2):252CrossRefGoogle Scholar
  8. 8.
    Guo W, Shi L, Filizola M, Weinstein H, Javitch JA (2005) Proc Natl Acad Sci USA 102(48):17495CrossRefGoogle Scholar
  9. 9.
    Waldhoer M, Fong J, Jones RM, Lunzer MM, Sharma SK, Kostenis E, Portoghese PS, Whistler JL (2005) Proc Natl Acad Sci USA 102(25):9050CrossRefGoogle Scholar
  10. 10.
    Filipek S, Krzysko KA, Fotiadis D, Liang Y, Saperstein DA, Engel A, Palczewski K (2004) Photochem Photobiol Sci 3(6):628CrossRefGoogle Scholar
  11. 11.
    Liang Y, Fotiadis D, Filipek S, Saperstein DA, Palczewski K, Engel A (2003) J Biol Chem 278:21655CrossRefGoogle Scholar
  12. 12.
    Jastrzebska B, Maeda T, Zhu L, Fotiadis D, Filipek S, Engel A, Stenkamp RE, Palczewski K (2004) J Biol Chem 279(52):54663CrossRefGoogle Scholar
  13. 13.
    Fotiadis D, Liang Y, Filipek S, Saperstein DA, Engel A, Palczewski K (2003) Nature 421(6919):127CrossRefGoogle Scholar
  14. 14.
    Teller DC, Okada T, Behnke CA, Palczewski K, Stenkamp RE (2001) Biochemistry 40:7761CrossRefGoogle Scholar
  15. 15.
    Kota P, Reeves PJ, Rajbhandary UL, Khorana HG (2006) Proc Natl Acad Sci USA 103(9):3054CrossRefGoogle Scholar
  16. 16.
    Pin JP, Kniazeff J, Liu J, Binet V, Goudet C, Rondard P, Prezeau L (2005) Febs J 272(12):2947CrossRefGoogle Scholar
  17. 17.
    Duthey B, Caudron S, Perroy J, Bettler B, Fagni L, Pin JP, Prezeau L (2002) J Biol Chem 277(5):3236CrossRefGoogle Scholar
  18. 18.
    Galvez T, Duthey B, Kniazeff J, Blahos J, Rovelli G, Bettler B, Prezeau L, Pin JP (2001) Embo J 20(9):2152CrossRefGoogle Scholar
  19. 19.
    Margeta-Mitrovic M, Jan YN, Jan LY (2001) Proc Natl Acad Sci USA 98:14643CrossRefGoogle Scholar
  20. 20.
    Goudet C, Kniazeff J, Hlavackova V, Malhaire F, Maurel D, Acher F, Blahos J, Prezeau L, Pin JP (2005) J Biol Chem 280(26):24380Google Scholar
  21. 21.
    Hlavackova V, Goudet C, Kniazeff J, Zikova A, Maurel D, Vol C, Trojanova J, Prezeau L, Pin JP, Blahos J (2005) Embo J 24(3):499CrossRefGoogle Scholar
  22. 22.
    Stenkamp RE, Teller DC, Palczewski K (2005) Arch Pharm (Weinheim) 338(5–6):209CrossRefGoogle Scholar
  23. 23.
    Weinstein H (2006) AAPS J 7(4):871CrossRefGoogle Scholar
  24. 24.
    Okada T, Fujiyoshi Y, Silow M, Navarro J, Landau EM, Shichida Y (2002) Proc Natl Acad Sci USA 99(9):5982CrossRefGoogle Scholar
  25. 25.
    Hassan SA, Mehler EL, Zhang D, Weinstein H (2003) Proteins 51:109CrossRefGoogle Scholar
  26. 26.
    Li XF, Hassan SA, Mehler EL (2005) Proteins Struct Funct Bioinform 60(3):464CrossRefGoogle Scholar
  27. 27.
    Mehler EL, Periole X, Hassan SA, Weinstein HJ (2002) Comput Aided Mol Des 16(11):841CrossRefGoogle Scholar
  28. 28.
    Okada T, Sugihara M, Bondar AN, Elstner M, Entel P, Buss V (2004) J Mol Biol 342(2):571CrossRefGoogle Scholar
  29. 29.
    Periole X, Ceruso MA, Mehler EL (2004) Biochemistry 43(22):6858CrossRefGoogle Scholar
  30. 30.
    Resat H, Mezei M (1994) J Am Chem Soc 116:7451CrossRefGoogle Scholar
  31. 31.
    Resat H, Mezei M (1996) Biophys J 71(3):1179Google Scholar
  32. 32.
    Marrone TJ, Resat H, Hodge CN, Chang C-H, McCammon JA (1998) Protein Sci 7:573CrossRefGoogle Scholar
  33. 33.
    Berendsen HJC, van der Spoel D, van Drunen R (1995) Comp Phys Comm 91:43CrossRefGoogle Scholar
  34. 34.
    Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) J Comput Chem 26(16):1701CrossRefGoogle Scholar
  35. 35.
    Tajkhorshid E, Baudry J, Schulten K, Suhai S (2000) Biophys J 78(2):683Google Scholar
  36. 36.
    Tajkhorshid E, Paizs B, Suhai S (1997) J Phys Chem B 101:8021CrossRefGoogle Scholar
  37. 37.
    Tajkhorshid E, Suhai S (1999) J Phys Chem B 103:5581CrossRefGoogle Scholar
  38. 38.
    Nina M, Roux B, Smith J (1995) Biophys J 68:25Google Scholar
  39. 39.
    Tieleman DP, Berendsen HJ (1998) Biophys J 74(6):2786Google Scholar
  40. 40.
    Tieleman DP, Forrest LR, Sansom MS, Berendsen HJ (1998) Biochemistry 37(50):17554CrossRefGoogle Scholar
  41. 41.
    Sankararamakrishnan R, Weinstein H (2000) Biophys J 79(5):2331Google Scholar
  42. 42.
    Sankararamakrishnan R, Weinstein H (2004) J Phys Chem B 108:11802CrossRefGoogle Scholar
  43. 43.
    Sankararamakrishnan R, Weinstein H (2002) J Phys Chem B 106:209CrossRefGoogle Scholar
  44. 44.
    Visiers I, Ballesteros JA, Weinstein H (2002) Meth Enzymol 343:329Google Scholar
  45. 45.
    Fanelli F, De Benedetti PG (2005) Chem Rev 105(9):3297CrossRefGoogle Scholar
  46. 46.
    Berger O, Edholm O, Jahnig F (1997) Biophys J 72:2002CrossRefGoogle Scholar
  47. 47.
    Darden T, York D, Pederson L (1993) J Chem Phys 98:10089CrossRefGoogle Scholar
  48. 48.
    Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) J Comput Chem 18:1463CrossRefGoogle Scholar
  49. 49.
    Berendsen HJC, Postma JPM, Gunsteren WF, Hermans J (1981) Intermolecular forces. Riedel, DordrechtGoogle Scholar
  50. 50.
    van Aalten DM, Amadei A, Linssen AB, Eijsink VG, Vriend G, Berendsen HJ (1995) Proteins 22(1):45CrossRefGoogle Scholar
  51. 51.
    Visiers I, Braunheim BB, Weinstein H (2000) Protein Eng 13(9):603CrossRefGoogle Scholar
  52. 52.
    Mezei M, Filizola, M (2006) J Comp Aid Mol Des. 20(2):97Google Scholar
  53. 53.
    Pitman MC, Grossfield A, Suits F, Feller SE (2005) J Am Chem Soc 127(13):4576CrossRefGoogle Scholar
  54. 54.
    Saam J, Tajkhorshid E, Hayashi S, Schulten K (2002) Biophys J 83(6):3097Google Scholar
  55. 55.
    Huber T, Botelho AV, Beyer K, Brown MF (2004) Biophys J 86(4):2078Google Scholar
  56. 56.
    Faraldo-Gomez JD, Forrest LR, Baaden M, Bond PJ, Domene C, Patargias G, Cuthbertson J, Sansom MS (2004) Proteins 57(4):783CrossRefGoogle Scholar
  57. 57.
    Schlegel B, Sippl W, Holtje HD (2005) J Mol Model (Online) 12(1):49CrossRefGoogle Scholar
  58. 58.
    Crozier PS, Stevens MJ, Forrest LR, Woolf TB (2003) J Mol Biol 333(3):493CrossRefGoogle Scholar
  59. 59.
    Fong SL, Tsin AT, Bridges CD, Liou GI (1982) Methods Enzymol 81:133Google Scholar
  60. 60.
    Petrache HI, Dodd SW, Brown MF (2000) Biophys J 79:3172Google Scholar
  61. 61.
    Hayward S, Berendsen HJ (1998) Proteins 30(2):144CrossRefGoogle Scholar
  62. 62.
    Farrens DL, Altenbach C, Yang K, Hubbell WL, Khorana HG (1996) Science 274(5288):768CrossRefGoogle Scholar
  63. 63.
    Borhan B, Souto ML, Imai H, Shichida Y, Nakanishi K (2000) Science 288(5474):2209CrossRefGoogle Scholar
  64. 64.
    Ballesteros JA, Weinstein H (1995) Meth Neurosci 25:366CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  1. 1.Department of Physiology & BiophysicsWeill Medical College of Cornell UniversityNew YorkUSA
  2. 2.HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational BiomedicineWeill Medical College of Cornell UniversityNew YorkUSA

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