What induces pocket openings on protein surface patches involved in protein–protein interactions?

Article

Abstract

We previously showed for the proteins BCL-XL, IL-2, and MDM2 that transient pockets at their protein–protein binding interfaces can be identified by applying the PASS algorithm to molecular dynamics (MD) snapshots. We now investigated which aspects of the natural conformational dynamics of proteins induce the formation of such pockets. The pocket detection protocol was applied to three different conformational ensembles for the same proteins that were extracted from MD simulations of the inhibitor bound crystal conformation in water and the free crystal/NMR structure in water and in methanol. Additional MD simulations studied the impact of backbone mobility. The more efficient CONCOORD or normal mode analysis (NMA) techniques gave significantly smaller pockets than MD simulations, whereas tCONCOORD generated pockets comparable to those observed in MD simulations for two of the three systems. Our findings emphasize the influence of solvent polarity and backbone rearrangements on the formation of pockets on protein surfaces and should be helpful in future generation of transient pockets as putative ligand binding sites at protein–protein interfaces.

Keywords

Binding pocket CONCOORD Molecular dynamics simulation Normal mode analysis Protein–protein interaction inhibition Structure-based drug design tCONCOORD 

Supplementary material

10822_2008_9239_MOESM1_ESM.pdf (7.1 mb)
MOESM1 (PDF 7238 kb)

References

  1. 1.
    Brady GP, Stouten PFW (2000) J Comput Aided Mol Des 14:383. doi:10.1023/A:1008124202956 CrossRefGoogle Scholar
  2. 2.
    Hendlich M, Rippmann F, Barnickel G (1997) J Mol Graph Model 15:359. doi:10.1016/S1093-3263(98)00002-3 CrossRefGoogle Scholar
  3. 3.
    Levitt DG, Banaszak LJ (1992) J Mol Graph 10:229. doi:10.1016/0263-7855(92)80074-N CrossRefGoogle Scholar
  4. 4.
    Laskowski RA (1995) J Mol Graph 13:323. doi:10.1016/0263-7855(95)00073-9 CrossRefGoogle Scholar
  5. 5.
    Laskowski RA, Luscombe NM, Swindells MB, Thornton JM (1996) Protein Sci 5:2438Google Scholar
  6. 6.
    Liang J, Edelsbrunner H, Woodward C (1998) Protein Sci 7:1884CrossRefGoogle Scholar
  7. 7.
    Nayal M, Honig B (2006) Proteins 63:892. doi:10.1002/prot.20897 CrossRefGoogle Scholar
  8. 8.
    Landon MR, Lancia DR Jr, Yu J et al (2007) J Med Chem 50:1231. doi:10.1021/jm061134b CrossRefGoogle Scholar
  9. 9.
    Goodford PJ (1985) J Med Chem 28:849. doi:10.1021/jm00145a002 CrossRefGoogle Scholar
  10. 10.
    Laurie ATR, Jackson RM (2005) Bioinformatics 21:1908. doi:10.1093/bioinformatics/bti315 CrossRefGoogle Scholar
  11. 11.
    Berg T (2003) Angew Chem Int Ed Engl 42:2462. doi:10.1002/anie.200200558 CrossRefGoogle Scholar
  12. 12.
    Yin H, Hamilton AD (2005) Angew Chem Int Ed Engl 44:4130. doi:10.1002/anie.200461786 CrossRefGoogle Scholar
  13. 13.
    Wells JA, McClendon CL (2007) Nature 450:1001. doi:10.1038/nature06526 CrossRefGoogle Scholar
  14. 14.
    Ryan KM, Phillips AC, Vousden KH (2001) Curr Opin Cell Biol 13:332. doi:10.1016/S0955-0674(00)00216-7 CrossRefGoogle Scholar
  15. 15.
    Michael D, Oren M (2003) Semin Cancer Biol 13:49. doi:10.1016/S1044-579X(02)00099-8 CrossRefGoogle Scholar
  16. 16.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) Science 253:49. doi:10.1126/science.1905840 CrossRefGoogle Scholar
  17. 17.
    Zheleva DI, Lane DP, Fischer PM (2003) Mini Rev Med Chem 3:257. doi:10.2174/1389557033488178 CrossRefGoogle Scholar
  18. 18.
    Fry DC, Emerson SD, Palme S et al (2004) J Biomol NMR 30:163. doi:10.1023/B:JNMR.0000048856.84603.9b CrossRefGoogle Scholar
  19. 19.
    Vassilev LT, Vu BT, Graves B et al (2004) Science 303:844. doi:10.1126/science.1092472 CrossRefGoogle Scholar
  20. 20.
    Grasberger BL, Lu T, Schubert C et al (2005) J Med Chem 48:909. doi:10.1021/jm049137g CrossRefGoogle Scholar
  21. 21.
    Arkin MR, Wells JA (2004) Nat Rev Drug Discov 3:301. doi:10.1038/nrd1343 CrossRefGoogle Scholar
  22. 22.
    Apostolakis J, Plueckthun A, Caflisch A (1997) J Comput Chem 19:21. doi :10.1002/(SICI)1096-987X(19980115)19:1<21::AID-JCC2>3.0.CO;2-0CrossRefGoogle Scholar
  23. 23.
    Zacharias M (2004) Proteins 54:759. doi:10.1002/prot.10637 CrossRefGoogle Scholar
  24. 24.
    Meiler J, Baker D (2006) Proteins 65:538. doi:10.1002/prot.21086 CrossRefGoogle Scholar
  25. 25.
    Sousa FS, Fernandes PA, Ramos MJ (2006) Proteins 65:15. doi:10.1002/prot.21082 CrossRefGoogle Scholar
  26. 26.
    Lin JH, Perryman AL, Schames JR, McCammon JA (2002) J Am Chem Soc 124:5632. doi:10.1021/ja0260162 CrossRefGoogle Scholar
  27. 27.
    Amaro RE, Baron R, McCammon JA (2008) An improved relaxed complex scheme for receptor flexibility in computer-aided drug design. J Comput Aided Mol Des. doi:10.1007/s10822-007-9159-2
  28. 28.
    Bowman AL, Nikolovska-Coleska Z, Zhong H et al (2007) J Am Chem Soc 129:12809. doi:10.1021/ja073687x CrossRefGoogle Scholar
  29. 29.
    Eyrisch S, Helms V (2007) J Med Chem 50:3457. doi:10.1021/jm070095g CrossRefGoogle Scholar
  30. 30.
    Morris GM, Goodsell DS, Halliday RS et al (1998) J Comput Chem 19:1639. doi :10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-BCrossRefGoogle Scholar
  31. 31.
    Lide DR (2005) Handbook of chemistry and physics. CRC Press, Boca Raton, FLGoogle Scholar
  32. 32.
    Alonso DO, Daggett V (1995) J Mol Biol 247:501. doi:10.1006/jmbi.1994.0156 CrossRefGoogle Scholar
  33. 33.
    Kovacs H, Mark AE, Johansson J, van Gunsteren WF (1995) J Mol Biol 247:808Google Scholar
  34. 34.
    de Groot BL, van Aalten DMF, Scheek RM et al (1997) Proteins 29:240. doi :10.1002/(SICI)1097-0134(199710)29:2<240::AID-PROT11>3.0.CO;2-OCrossRefGoogle Scholar
  35. 35.
    Seelinger D, Haas J, de Groot BL (2007) Structure 15:1482. doi:10.1016/j.str.2007.09.017 CrossRefGoogle Scholar
  36. 36.
    Brooks B, Karplus M (1983) Proc Natl Acad Sci USA 80:6571. doi:10.1073/pnas.80.21.6571 CrossRefGoogle Scholar
  37. 37.
    Levitt M, Sander C, Stern PS (1985) J Mol Biol 181:423. doi:10.1016/0022-2836(85)90230-X CrossRefGoogle Scholar
  38. 38.
    Ma J (2005) Structure 13:373. doi:10.1016/j.str.2005.02.002 CrossRefGoogle Scholar
  39. 39.
    van Aalten DMF, de Groot BL, Findlay JBC et al (1997) J Comput Chem 18:169. doi :10.1002/(SICI)1096-987X(19970130)18:2<169::AID-JCC3>3.0.CO;2-TCrossRefGoogle Scholar
  40. 40.
    Zheng W, Doniach S (2003) Proc Natl Acad Sci USA 100:13253. doi:10.1073/pnas.2235686100 CrossRefGoogle Scholar
  41. 41.
    Bruccoleri RE, Karplus M, McCammon JA (1986) Biopolymers 25:1767. doi:10.1002/bip.360250916 CrossRefGoogle Scholar
  42. 42.
    Fu X, Apgar J, Keating AE (2007) J Mol Biol 371:1099. doi:10.1016/j.jmb.2007.04.069 CrossRefGoogle Scholar
  43. 43.
    Barrett CP, Hall BA, Noble ME (2004) Acta Crystallogr D Biol Crystallogr 60:2280. doi:10.1107/S0907444904019171 CrossRefGoogle Scholar
  44. 44.
    Espinoza-Fonseca LM, Trujillo-Ferrara JG (2006) Biopolymers 83:365. doi:10.1002/bip.20566 CrossRefGoogle Scholar
  45. 45.
    Berman HM, Westbrook J, Feng Z et al (2000) Nucleic Acids Res 28:235. doi:10.1093/nar/28.1.235 CrossRefGoogle Scholar
  46. 46.
    de Bakker PI, DePristo MA, Burke DF, Blundell TL (2003) Proteins 51:21. doi:10.1002/prot.10235 CrossRefGoogle Scholar
  47. 47.
    Lindahl E, Hess B, van der Spoel D (2001) J Mol Model 7:306Google Scholar
  48. 48.
    Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) J Am Chem Soc 118:11225. doi:10.1021/ja9621760 CrossRefGoogle Scholar
  49. 49.
    Jorgensen WL, Chandrasekhar J, Madura JD et al (1983) J Chem Phys 79:926. doi:10.1063/1.445869 CrossRefGoogle Scholar
  50. 50.
    Darden T, York D, Pedersen L (1993) J Chem Phys 98:10089. doi:10.1063/1.464397 CrossRefGoogle Scholar
  51. 51.
    Berendsen HJC, Postma JPM, van Gunsteren WF et al (1984) J Chem Phys 81:3684. doi:10.1063/1.448118 CrossRefGoogle Scholar
  52. 52.
    Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) J Comput Chem 18:1463. doi :10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-HCrossRefGoogle Scholar
  53. 53.
    Humphrey W, Dalke A, Schulten K (1996) J Mol Graph 14:33. doi:10.1016/0263-7855(96)00018-5 CrossRefGoogle Scholar
  54. 54.
    Engh RA, Huber R (1991) Acta Crystallogr A 47:392. doi:10.1107/S0108767391001071 CrossRefGoogle Scholar
  55. 55.
    Kohlbacher O, Lenhof HP (2000) Bioinformatics 16:815. doi:10.1093/bioinformatics/16.9.815 CrossRefGoogle Scholar
  56. 56.
    Sanner MF (1999) J Mol Graph Model 17:57Google Scholar
  57. 57.
    Gasteiger J, Marsili M (1980) Tetrahedron 36:3219. doi:10.1016/0040-4020(80)80168-2 CrossRefGoogle Scholar
  58. 58.
    McCoy MA, Gesell JJ, Senior MM, Wyss DF (2003) Proc Natl Acad Sci USA 100:1645. doi:10.1073/pnas.0334477100 CrossRefGoogle Scholar
  59. 59.
    Uhrinova S, Uhrin D, Powers H et al (2005) J Mol Biol 350:587. doi:10.1016/j.jmb.2005.05.010 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  1. 1.Center for BioinformaticsSaarbrueckenGermany

Personalised recommendations