Journal of Computer-Aided Molecular Design

, Volume 25, Issue 1, pp 81–101

Molecular and structural determinants of adamantyl susceptibility to HLA-DRs allelic variants: an in silico approach to understand the mechanism of MLEs

Article

Abstract

Class II major histocompatibility complex (MHC II) molecules as expressed by antigen-presenting cells are heterodimeric cell-surface glycoprotein receptors that are fundamental in initiating and propagating an immune response by presenting tumor-associated antigenic peptides to CD4+/TH cells. The loading efficiency of such peptides can be improved by small organic compounds (MHC Loading Enhancers—MLEs), that convert the non-receptive peptide conformation of MHC II to a peptide-receptive conformation. In a reversible reaction, these compounds open up the binding site of MHC II molecules by specific interactions with a yet undefined pocket. Here, we performed molecular docking and molecular dynamics simulation studies of adamantyl compounds on the predicted cavity around the P1 pocket of 2 allelic variants of HLA-DRs. The purpose was to investigate the suitability of adamantyl compounds as MLEs at the dimorphic β86 position. Docking studies revealed that besides numerous molecular interactions formed by the adamantyl compounds, Asnβ82, Tyrβ83, and Thrβ90 are the crucial amino acid residues that are characterized as the “sensors” of peptide loading. Molecular dynamics simulation studies exposed the dynamical structural changes that HLA-DRs adopted as a response to binding of 3-(1-adamantyl)-5-hydrazidocarbonyl-1H-pyrazole (AdCaPy). The conformations of AdCaPy complexed with the Glyβ86 HLA-DR allelic variant are well correlated with the stabilized form of peptide-loaded HLA-DRs, further confirming the role of AdCaPy as a MLE. Hydrogen bonding interaction analysis clearly demonstrated that after making suitable contacts with AdCaPy, HLA-DR changes its local conformation. However, AdCaPy complexed with HLA-DR having Valβ86 at the dimorphic position did not accommodate AdCaPy as MLE due to steric hindrance caused by the valine.

Keywords

Major histocompatibility complex Human leucocytes antigen Polymorphism Adamantyl compounds Docking Molecular dynamics simulation 

References

  1. 1.
    Corthay A, Skovseth DK, Lundin KU, Røsjø E, Omholt H, Hofgaard PO, Haraldsen G, Bogen B (2005) Immunity 22:371–383CrossRefGoogle Scholar
  2. 2.
    Stern LJ, Potolicchio I, Santambrogio L (2006) Curr Opin Immunol 18:64–69CrossRefGoogle Scholar
  3. 3.
    Watts C (2001) Curr Opin Immunol 13:26–31CrossRefGoogle Scholar
  4. 4.
    McFarland BJ, Beeson C (2002) Med Res Rev 22:168–203CrossRefGoogle Scholar
  5. 5.
    Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC (1994) Nature 368:215–221CrossRefGoogle Scholar
  6. 6.
    Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC (1993) Nature 364:33–39CrossRefGoogle Scholar
  7. 7.
    Hansen TH, Lybarger L, Yu L, Mitaksov V, Fremont DH (2005) Immunol Rev 207:100–111CrossRefGoogle Scholar
  8. 8.
    Carven GJ, Chitta S, Hilgert I, Rushe MM, Baggio RF, Palmer M, Arenas JE, Strominger JL, Horejsi V, Santambrogio L (2004) J Biol Chem 279:16561–16570CrossRefGoogle Scholar
  9. 9.
    Painter CA, Cruz A, López GE, Stern LJ, Zavala-Ruiz Z (2008) PLoS ONE 3:e2403CrossRefGoogle Scholar
  10. 10.
    Zarutskie JA, Sato AK, Rushe MM, Chan IC, Lomakin A, Benedek GB, Stern LJ (1999) Biochemistry 38:5878–5887CrossRefGoogle Scholar
  11. 11.
    Chou CL, Sadegh-Nasseri S (2000) J Exp Med 192:1697–1706CrossRefGoogle Scholar
  12. 12.
    Rabinowitz JD, Vrljic M, Kasson PM, Liang MN, Busch R, Boniface JJ, Davis MM, McConnell HM (1998) Immunity 9:699–710CrossRefGoogle Scholar
  13. 13.
    Schmitt L, Boniface JJ, Davis MM, McConnell HM (1999) J Mol Biol 286:207–218CrossRefGoogle Scholar
  14. 14.
    Kalams SA, Walker BD (1998) J Exp Med 188:2199–2204CrossRefGoogle Scholar
  15. 15.
    Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H (1998) J Exp Med 188:2357–2368CrossRefGoogle Scholar
  16. 16.
    Marin-Esteban V, Falk K, Rötzschke O (2003) J Autoimmune 20:63–69CrossRefGoogle Scholar
  17. 17.
    Marin-Esteban V, Falk K, Rotzschke O (2004) J Biol Chem 279:50684–50690CrossRefGoogle Scholar
  18. 18.
    Nicholson MJ, Moradi B, Seth NP, Xing X, Cuny GD, Stein RL, Wucherpfennig KW (2006) J Immunol 176:4208–4220Google Scholar
  19. 19.
    Hopner S, Dickhaut K, Hofstatter M, Kramer H, Ruckerl D, Soderhall JA, Gupta S, Marin-Esteban V, Kuhne R, Freund C (2006) J Biol Chem 281:38535–38542CrossRefGoogle Scholar
  20. 20.
    Gupta S, Höpner S, Rupp B, Günther S, Dickhaut K, Agarwal N, Cardoso MC, Kühne R, Wiesmüller KH, Jung G (2008) PLoS ONE 3:e1814CrossRefGoogle Scholar
  21. 21.
    Falk K, Lau JM, Santambrogio L, Esteban VM, Puentes F, Rötzschke O, Strominger JL (2002) J Biol Chem 277:2709–2715CrossRefGoogle Scholar
  22. 22.
    Jones EY, Fugger L, Strominger JL, Siebold C (2006) Nat Rev Immunol 6:271–282CrossRefGoogle Scholar
  23. 23.
    Pinet V, Vergelli M, Martini R, Bakke O, Long EO (1995) Nat 375:603–606CrossRefGoogle Scholar
  24. 24.
    Vergelli M, Pinet V, Vogt AB, Kalbus M, Malnati M, Riccio P, Long EO, Martin R (1997) Eur J Immunol 27:941–951CrossRefGoogle Scholar
  25. 25.
    Santambrogio L, Sato AK, Carven GJ, Belyanskaya SL, Strominger JL, Stern LJ (1999) Proc Natl Acad Sci 96:15056–15061CrossRefGoogle Scholar
  26. 26.
    Santambrogio L, Sato AK, Fischer FR, Dorf ME, Stern LJ (1999) Proc Natl Acad Sci 96:15050–15055CrossRefGoogle Scholar
  27. 27.
    Dickhaut K, Hoepner S, Eckhard J, Wiesmueller KH, Schindler L, Jung G, Falk K, Roetzschke O (2009) PLoS One 4:e6811CrossRefGoogle Scholar
  28. 28.
    Warren GL, Andrews CW, Capelli AM, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S (2006) J Med Chem 49:5912–5931CrossRefGoogle Scholar
  29. 29.
    International hwtcTGoogle Scholar
  30. 30.
    Gasteiger J, Marsili M (1980) Tetrahedron 36:3219–3228CrossRefGoogle Scholar
  31. 31.
    Clark M, Cramer RD, Opdenbosch NV (1989) J Comp Chem 10:982–1012CrossRefGoogle Scholar
  32. 32.
    Berman HM (2007) Acta Cryst 64:88–95Google Scholar
  33. 33.
    Murthy VL, Stern LJ (1997) Struct 5:1385–1396CrossRefGoogle Scholar
  34. 34.
    Stern LJ, Wiley DC (1994) Structure 2:245–251CrossRefGoogle Scholar
  35. 35.
    Smith KJ, Pyrdol J, Gauthier L, Wiley DC, Wucherpfennig KW (1998) J Exp Med 188:1511–1520CrossRefGoogle Scholar
  36. 36.
    Li Y, Li H, Martin R, Mariuzza RA (2000) J Mol Biol 304:177–188CrossRefGoogle Scholar
  37. 37.
    Thomsen R, Christensen MH (2006) J Med Chem 49:3315–3321CrossRefGoogle Scholar
  38. 38.
    Z M (1992) Spinger, BerlinGoogle Scholar
  39. 39.
    Michalewiez ZFD (2000) How to solve it: modern heuristics. Spinger, BerlinGoogle Scholar
  40. 40.
    Gehlhaar DK, Verkhivker G, Rejto PA, Fogel DB, Fogel LJ, Freer ST (1995) In: McDonnell JR, Reynolds RG, Fogel DB (eds) Proceedings of the fourth international conference on evolutionary programming. Massachusetts Institute of Technology, USAGoogle Scholar
  41. 41.
    Gehlhaar DK, Bouzida D, Rejto PA (1998) In: Porto VW, Saravanan N, Waagen DE, Eiben AE (eds) Proceedings of the seventh international conference on evolutionary programming. Springer, USAGoogle Scholar
  42. 42.
    Yang JM, Chen CC (2004) Proteins 55:288–304CrossRefGoogle Scholar
  43. 43.
    Aaqvist J (1990) J Phys Chem 94:8021–8024CrossRefGoogle Scholar
  44. 44.
    Case DA, Cheatham TE III, Darden T, Gohlke H, Luo R, Merz KM Jr, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) J Comp Chem 26:1668–1688CrossRefGoogle Scholar
  45. 45.
    Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comp Chem 25:1157–1174CrossRefGoogle Scholar
  46. 46.
    Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) J Comp Phys 103:8577–8593Google Scholar
  47. 47.
    Ryckaert JP, Ciccotti G, Berendsen HJC (1977) J Comp Phys 23:327–341CrossRefGoogle Scholar
  48. 48.
    Humphrey W, Dalke A, Schulten K (1996) J Mol Graph 14:33–38CrossRefGoogle Scholar
  49. 49.
    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) J Comp Chem 25:1605–1612CrossRefGoogle Scholar
  50. 50.
    O’Sullivan D, Arrhenius T, Sidney J, Del Guercio MF, Albertson M, Wall M, Oseroff C, Southwood S, Colon SM, Gaeta FC (1991) J Immunol 147:2663–2669Google Scholar
  51. 51.
    Geluk A, Van Meijgaarden KE, Southwood S, Oseroff C, Drijfhout JW, De Vries RR, Ottenhoff TH, Sette A (1994) J Immunol 152:5742–5748Google Scholar
  52. 52.
    Falk K, Rötzschke O, Stevanovíc S, Jung G, Rammensee HG (1994) Immunogenetics 39:230–242CrossRefGoogle Scholar
  53. 53.
    Vaught A (1996) Linux J 1996:7Google Scholar
  54. 54.
    Yaneva R, Springer S, Zacharias M (2009) Biopolymers 91:14–27CrossRefGoogle Scholar
  55. 55.
    Call MJ, Xing X, Cuny GD, Seth NP, Altmann DM, Fugger L, Krogsgaard M, Stein RL, Wucherpfennig KW (2009) J Immunol 182:6342–6352CrossRefGoogle Scholar
  56. 56.
    Toes REM, Ossendorp F, Offringa R, Melief CJM (1999) J Exp Med 189:753–756CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological SciencesUniversity of KarachiKarachiPakistan
  2. 2.H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological SciencesUniversity of KarachiKarachiPakistan

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