Journal of Molecular Modeling

, 20:2472 | Cite as

Conformational analysis of a polyconjugated protein-binding ligand by joint quantum chemistry and polarizable molecular mechanics. Addressing the issues of anisotropy, conjugation, polarization, and multipole transferability

  • Elodie Goldwaser
  • Benoit de Courcy
  • Luc Demange
  • Christiane Garbay
  • Françoise Raynaud
  • Reda Hadj-Slimane
  • Jean-Philip Piquemal
  • Nohad Gresh
Original Paper


We investigate the conformational properties of a potent inhibitor of neuropilin-1, a protein involved in cancer processes and macular degeneration. This inhibitor consists of four aromatic/conjugated fragments: a benzimidazole, a methylbenzene, a carboxythiourea, and a benzene-linker dioxane, and these fragments are all linked together by conjugated bonds. The calculations use the SIBFA polarizable molecular mechanics procedure. Prior to docking simulations, it is essential to ensure that variations in the ligand conformational energy upon rotations around its six main-chain torsional bonds are correctly represented (as compared to high-level ab initio quantum chemistry, QC). This is done in two successive calibration stages and one validation stage. In the latter, the minima identified following independent stepwise variations of each of the six main-chain torsion angles are used as starting points for energy minimization of all the torsion angles simultaneously. Single-point QC calculations of the minimized structures are then done to compare their relative energies ΔE conf to the SIBFA ones. We compare three different methods of deriving the multipoles and polarizabilities of the central, most critical moiety of the inhibitor: carboxythiourea (CTU). The representation that gives the best agreement with QC is the one that includes the effects of the mutual polarization energy E pol between the amide and thioamide moieties. This again highlights the critical role of this contribution. The implications and perspectives of these findings are discussed.


Polarizable force fields Multipoles Conjugation 



We wish to thank the Grand Equipement National de Calcul Intensif (GENCI): Institut du Developpement et des Ressources en Informatique Scientifique (IDRIS), Centre Informatique de l’Enseignement Superieur (CINES), France, project no. x2009-075009), and the Centre de Ressources Informatiques de Haute Normandie (CRIHAN, Rouen, France), project 1998053.

We wish to acknowledge a CIFRE grant allotted to Elodie Goldwaser in the course of her Ph.D. thesis.

We are pleased to thank Drs. Lucia Borriello and Pascal Dao for enriching discussions during the course of this work.

Supplementary material

894_2014_2472_MOESM1_ESM.doc (356 kb)
S1 Intermolecular interaction energies (kcal/mol) of water with sites in CTU, with a range of interaction distances that are shorter than the equilibrium distance considered. The energy contributions are listed as pairs of rows: the first row corresponds to the RVS values and the second to the SIBFA ones. The distances given in the first row of results are in Å. (DOC 355 kb)
894_2014_2472_MOESM2_ESM.doc (50 kb)
S2 Torsion angles (in degrees) of lig-47 in its energy-minimized conformations. (DOC 49 kb)
894_2014_2472_MOESM3_ESM.doc (244 kb)
S3 Construction of CTU by assembling thioamide and amide fragments. Intermolecular interaction energies (kcal/mol) of water with sites in CTU are shown, with a range of distances that are shorter than equilibrium distance considered. The energy contributions are listed as pairs of rows: the first row corresponds to the RVS values and the second to the SIBFA ones. The distances given in the first row of results are in Å. (DOC 243 kb)
894_2014_2472_MOESM4_ESM.doc (60 kb)
S4 Construction of CTU by assemblingsp 2 amine, thioaldehyde, and aldehyde fragments. Intermolecular interaction energies (kcal/mol) and the various contributions to those energies in the binding of a probe water molecule with sites in CTU. The energy contributions are listed as pairs of rows: the first row corresponds to the RVS values and the second to the SIBFA ones. Distances given in the first row of results are in Å. (DOC 60 kb)
894_2014_2472_MOESM5_ESM.doc (383 kb)
S5 Construction of CTU by assemblingsp 2 amine, thioaldehyde, and aldehyde fragments. Variations in the conformational energy of lig-47 as functions of the torsion anglesφ1 andφ3–φ7 are shown. (DOC 383 kb)


  1. 1.
    Djordjevic S, Driscoll PC (2013) Drug Discov Today 18:44CrossRefGoogle Scholar
  2. 2.
    Allain B, Jarray R, Borriello L, Leforban B, Dufour S, Liu W, Pamonsinlapatham P, Bianco S, Larghero J, Hadj-Slimane R, Garbay C, Raynaud F, Lepelletier Y (2012) Cell Signal 24:214CrossRefGoogle Scholar
  3. 3.
    Van der Kooi CW, Jusino MA, Perman B, Neau DB, Bellamy HD, Leahy D (2007) J Proc Natl Acad Sci USA 104:6152Google Scholar
  4. 4.
    Jarvis A, Allerston CK, Jia H, Herzog B, Garza-Garcia A, Winfield N, Ellard K, Aqil R, Lynch R, Chapman C, Hartzoulakis B, Nally J, Stewart M, Cheng L, Menon M, Tickner M, Djordjevic S, Driscoll PC, Zachary I, Selwood DL (2010) J Med Chem 53:2215CrossRefGoogle Scholar
  5. 5.
    Jain A (2003) J Med Chem 46:499CrossRefGoogle Scholar
  6. 6.
    Gresh N, Claverie P, Pullman A (1984) Theor Chim Acta 66:1Google Scholar
  7. 7.
    Gresh N (1995) J Comput Chem 16:856CrossRefGoogle Scholar
  8. 8.
    Gresh N (2006) Curr Pharm Des 12:2121CrossRefGoogle Scholar
  9. 9.
    Gresh N, Cisneros GA, Darden TA, Piquemal J (2007) J Chem Theory Comput 3:1960CrossRefGoogle Scholar
  10. 10.
    Piquemal J-P, Chevreau H, Gresh N (2007) J Chem Theory Comput 3:824CrossRefGoogle Scholar
  11. 11.
    Silvi B, Savin A (1994) Nature 371:683CrossRefGoogle Scholar
  12. 12.
    Piquemal J-P, Pilme J, Parisel O, Gerard H, Fourre I, Berges J, Gourlaouen C, De La Lande A, Van Severen M-C, Silvi B (2008) Int J Quantum Chem 108:1951CrossRefGoogle Scholar
  13. 13.
    Chaudret R, Gresh N, Cisneros GA, Scemama A, Piquemal J-P (2013) Can J Chem 91:1CrossRefGoogle Scholar
  14. 14.
    Dunning TH (1989) J Chem Phys 90:1007CrossRefGoogle Scholar
  15. 15.
    Feller D (1996) J Comput Chem 17:1571CrossRefGoogle Scholar
  16. 16.
    Frisch MJ, Trucks GW, Schlegel HB et al. (2009) Gaussian 09, revision A.1. Gaussian, Inc., WallingfordGoogle Scholar
  17. 17.
    Stevens WJ, Fink W (1987) Chem Phys Letts 139:15CrossRefGoogle Scholar
  18. 18.
    Schmidt MW, Baldridge KK, Boatz JA, Elbert ST, Gordon MS, Jensen JH, Koseki S, Matsunaga N, Nguyen KA, Su S, Windus TL, Dupuis M, Montgomery JA (1993) J Comput Chem 14:1347CrossRefGoogle Scholar
  19. 19.
    Stone A (1981) J Chem Phys Letts 83:233CrossRefGoogle Scholar
  20. 20.
    Stone AJ, Alderton M (1985) Mol Phys 56:1047CrossRefGoogle Scholar
  21. 21.
    Piquemal J-P, Gresh N, Giessner-Prettre C (2003) J Phys Chem A 107:10353CrossRefGoogle Scholar
  22. 22.
    Garmer DR, Stevens WJ (1989) J Phys Chem A 93:8263CrossRefGoogle Scholar
  23. 23.
    Gresh N, Kafafi SA, Truchon J-F, Salahub DR (2004) J Comput Chem 25:823CrossRefGoogle Scholar
  24. 24.
    Beachy MD, Chasman D, Murphy RB, Halgren TA, Friesner RA (1997) J Am Chem Soc 119:5908CrossRefGoogle Scholar
  25. 25.
    Evangelakis GA, Rizos JP, Lagaris IE, Demetropoulos IN (1987) Comput Phys Comm 46:401CrossRefGoogle Scholar
  26. 26.
    McInnes C (2007) Curr Op Chem Biol 11:494CrossRefGoogle Scholar
  27. 27.
    Cavasotto CN, Orry A (2007) J Curr Top Med Chem 7:1006CrossRefGoogle Scholar
  28. 28.
    Kroemer RT (2007) Curr Protein Pept Sci 8:312CrossRefGoogle Scholar
  29. 29.
    Irwin J (2008) J Comp-Aided Mol Des 22:193CrossRefGoogle Scholar
  30. 30.
    Sotriffer CA, Sanschagrin P, Matter H, Klebe G (2008) Proteins 73:395CrossRefGoogle Scholar
  31. 31.
    Gilson MK, Zhou HX (2007) Ann Rev Biophys Biomol Struct 36:21CrossRefGoogle Scholar
  32. 32.
    Schneider G (2010) Nat Rev Drug Discov 9:273CrossRefGoogle Scholar
  33. 33.
    Ren P, Ponder JW (2003) J Phys Chem B 107:5933CrossRefGoogle Scholar
  34. 34.
    Lee C, Yang W, Parr RG (1988) Phys Rev B37:785CrossRefGoogle Scholar
  35. 35.
    Becke A (1993) J Chem Phys 98:5648CrossRefGoogle Scholar
  36. 36.
    Grimme S (2006) J Comput Chem 27:1787CrossRefGoogle Scholar
  37. 37.
    Gloaguen E, de Courcy B, Piquemal J-P, Pilme J, Parisel O, Pollet R, Biswal HS, Piuzzi F, Tardivel B, Broquier M, Mons M (2010) J Am Chem Soc 132:11860CrossRefGoogle Scholar
  38. 38.
    van Mourik T (2008) J Chem Theory Comput 4:1610CrossRefGoogle Scholar
  39. 39.
    Head-Gordon M, Pople JA (1993) J Phys Chem 97:1147CrossRefGoogle Scholar
  40. 40.
    Head-Gordon M, Pople JA (1993) J Phys Chem 97:10250CrossRefGoogle Scholar
  41. 41.
    Meier RJ (1993) J Phys Chem 97:10248CrossRefGoogle Scholar
  42. 42.
    Meier RJ (2011) J Phys Chem 115:3604CrossRefGoogle Scholar
  43. 43.
    Klug R, Burcl R (2010) J Phys Chem A 114:6401CrossRefGoogle Scholar
  44. 44.
    Guo H, Gresh N, Roques BP, Salahub DR (2000) J Phys Chem B 104:9746CrossRefGoogle Scholar
  45. 45.
    Piquemal J-P, Chelli R, Procacci P, Gresh N (2007) J Phys Chem A 111:8170CrossRefGoogle Scholar
  46. 46.
    Zheng J, Yu T, Papajak E, Alecu IM, Mielke S, Truhlar DG (2011) Phys Chem Chem Phys 13:10885CrossRefGoogle Scholar
  47. 47.
    Tafipolsky M, Schmid R (2005) J Comput Chem 26:1579CrossRefGoogle Scholar
  48. 48.
    Rogalewicz F, Ohanessian G, Gresh N (2000) J Comput Chem 21:963CrossRefGoogle Scholar
  49. 49.
    Tiraboschi G, Fournié-Zaluski M-C, Roques B-P, Gresh N (2001) J Comput Chem 22:1038CrossRefGoogle Scholar
  50. 50.
    Gresh N, Shi GB (2004) J Comput Chem 25:160CrossRefGoogle Scholar
  51. 51.
    Antony J, Piquemal J-P, Gresh N (2005) J Comput Chem 26:1131CrossRefGoogle Scholar
  52. 52.
    Courcy B, Piquemal J-P, Garbay C, Gresh N (2010) J Am Chem Soc 132:3312CrossRefGoogle Scholar
  53. 53.
    Gresh N, Courcy B, Piquemal J-P, Foret J, Courtiol-Legourd, Salmon L (2011) J Phys Chem B 115:8304CrossRefGoogle Scholar
  54. 54.
    Jiao D, Golubkov PA, Darden TA, Ren P (2008) Proc Natl Acad Sci USA 105:6290Google Scholar
  55. 55.
    Jiao D, Zhang JJ, Duke RE, Li GH, Schnieders MJ, Ren P (2009) J Comput Chem 30:1701CrossRefGoogle Scholar
  56. 56.
    Ren P, Wu C, Ponder JW (2011) J Chem Theory Comput 7:3027CrossRefGoogle Scholar
  57. 57.
    Zhang J, Yang W, Piquemal J-P, Ren P (2012) J Chem Theory Comput 8:1314CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Elodie Goldwaser
    • 1
    • 2
  • Benoit de Courcy
    • 2
  • Luc Demange
    • 1
    • 4
  • Christiane Garbay
    • 1
  • Françoise Raynaud
    • 1
  • Reda Hadj-Slimane
    • 3
  • Jean-Philip Piquemal
    • 2
  • Nohad Gresh
    • 1
  1. 1.Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601, UFR BiomédicaleUniversité ParisDescartesParisFrance
  2. 2.Laboratoire de Chimie ThéoriqueSorbonne UniversitésParisFrance
  3. 3.Boulogne BillancourtFrance
  4. 4.Institut de Chimie de Nice (ICN), UMR 7272 CNRSUniversité de Nice Sophia-AntipolisNiceFrance

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