Journal of Computer-Aided Molecular Design

, Volume 28, Issue 4, pp 375–400 | Cite as

Free-energy perturbation and quantum mechanical study of SAMPL4 octa-acid host–guest binding energies

  • Paulius Mikulskis
  • Daniela Cioloboc
  • Milica Andrejić
  • Sakshi Khare
  • Joakim Brorsson
  • Samuel Genheden
  • Ricardo A. Mata
  • Pär SöderhjelmEmail author
  • Ulf RydeEmail author


We have estimated free energies for the binding of nine cyclic carboxylate guest molecules to the octa-acid host in the SAMPL4 blind-test challenge with four different approaches. First, we used standard free-energy perturbation calculations of relative binding affinities, performed at the molecular-mechanics (MM) level with TIP3P waters, the GAFF force field, and two different sets of charges for the host and the guest, obtained either with the restrained electrostatic potential or AM1-BCC methods. Both charge sets give good and nearly identical results, with a mean absolute deviation (MAD) of 4 kJ/mol and a correlation coefficient (R 2) of 0.8 compared to experimental results. Second, we tried to improve these predictions with 28,800 density-functional theory (DFT) calculations for selected snapshots and the non-Boltzmann Bennett acceptance-ratio method, but this led to much worse results, probably because of a too large difference between the MM and DFT potential-energy functions. Third, we tried to calculate absolute affinities using minimised DFT structures. This gave intermediate-quality results with MADs of 5–9 kJ/mol and R 2 = 0.6–0.8, depending on how the structures were obtained. Finally, we tried to improve these results using local coupled-cluster calculations with single and double excitations, and non-iterative perturbative treatment of triple excitations (LCCSD(T0)), employing the polarisable multipole interactions with supermolecular pairs approach. Unfortunately, this only degraded the predictions, probably because of a mismatch between the solvation energies obtained at the DFT and LCCSD(T0) levels.


Binding affinities Host–guest Free-energy perturbation Density-functional calculations CCSD(T) Polarisable multipole interactions 



This investigation has been supported by Grants from the Swedish research council (project 2010-5025). The computations were performed on computer resources provided by the Swedish National Infrastructure for Computing (SNIC) at Lunarc at Lund University and HPC2N at Umeå University. The collaboration between the Universities of Lund and Göttingen has been carried out within the framework of the International Research Training Group 1422 Metal Sites in Biomolecules—Structures, Regulation, Mechanisms and M. A. is supported through a Ph.D. scholarship in this International Research Training Group. D. C. thanks FEBS for a short-term fellowship. We are grateful to Prof. Stefan Grimme for providing us with the thermo program.

Supplementary material

10822_2014_9739_MOESM1_ESM.pdf (350 kb)
Supplementary material 1 (PDF 350 kb)


  1. 1.
    Gohlke H, Klebe G (2002) Angew Chem Int Ed 41:2644CrossRefGoogle Scholar
  2. 2.
    Jorgensen WL (2009) Acc Chem Res 42:724CrossRefGoogle Scholar
  3. 3.
    Zhou H-X, Gilson MK (2009) Chem Rev 109:4092CrossRefGoogle Scholar
  4. 4.
    Michel J, Essex JW (2010) J Comput Aided Mol Des 24:639CrossRefGoogle Scholar
  5. 5.
    Christ CD, Mark AE, van Gunsteren WF (2010) J Comput Chem 31:1569Google Scholar
  6. 6.
    Wereszczynski J, McCammon JA (2012) Quart Rev Biophys 45:1CrossRefGoogle Scholar
  7. 7.
    Halgren TA, Damm W (2001) Curr Opin Struct Biol 11:236CrossRefGoogle Scholar
  8. 8.
    Söderhjelm P, Ryde U (2009) J Phys Chem A 113:617CrossRefGoogle Scholar
  9. 9.
    Cavalli A, Carloni P, Recanatini M (2006) Chem Rev 106:3497CrossRefGoogle Scholar
  10. 10.
    Werner H.-J, Knowles P. J, Knizia G, Manby F. R, Schütz M et al (2012) MOLPRO,, version 2012.1, a package of ab initio programs. see
  11. 11.
    Raha K, Peters MB, Wang B, Yu N, Wollacott AM, Westerhoff LM, Merz KM (2007) Drug Discov Today 12:725CrossRefGoogle Scholar
  12. 12.
    Söderhjelm P, Kongsted J, Genheden S, Ryde U (2010) Interdiscip Sci Comput Life Sci 2:21–37CrossRefGoogle Scholar
  13. 13.
    Söderhjelm P, Genheden S, Ryde U (2012) Protein–ligand interactions. In: Gohlke H (ed) Methods and principles in medicinal chemistry, vol 53. Wiley-VCH, Weinheim, pp 121–143Google Scholar
  14. 14.
    Antony J, Grimme S (2012) J Comput Chem 33:1730CrossRefGoogle Scholar
  15. 15.
    Muddana HS, Varnado CD, Bielawski CW, Urbach AR, Isaacs L, Geballe MT, Gilson MK (2012) J Comput Aided Mol Des 26:475CrossRefGoogle Scholar
  16. 16.
    Muddana HS, Fenley AT, Mobley DL, Gilson MK (2014) Blind prediction of the host–guest binding affinities from the SAMPL4 challenge. J Comput-Aided Mol Design (in press)Google Scholar
  17. 17.
    Gibb CLD, Gibb BCJ (2004) Am Chem Soc 126:11408CrossRefGoogle Scholar
  18. 18.
    Sun H, Gibb CLD, Gibb BC (2008) Supramol Chem 20:141CrossRefGoogle Scholar
  19. 19.
    Gibb CLD, Gibb BC (2009) Tetrahedron 65:7240CrossRefGoogle Scholar
  20. 20.
    Grimme S, Antony J, Ehrlich S, Krieg H (2010) J Chem Phys 132:154104CrossRefGoogle Scholar
  21. 21.
    Grimme S (2012) Chem Eur J 18:9955CrossRefGoogle Scholar
  22. 22.
    Hampel C, Werner H-J (1996) J Chem Phys 104:6286CrossRefGoogle Scholar
  23. 23.
    Andrejić M, Mata RA, Ryde U, Söderhjelm P (2014) Chem Phys Chem (submitted)Google Scholar
  24. 24.
    Wang JM, Wolf RM, Caldwell KW, Kollman PA, Case DA (2004) J Comput Chem 25:1157–1174CrossRefGoogle Scholar
  25. 25.
    Jorgensen WL, Chandrasekhar J, Madura JD, Impley RW, Klein ML (1983) J Chem Phys 79:926–935CrossRefGoogle Scholar
  26. 26.
    Case DA, Darden TA, Cheatham TE III, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts BP, Wang B, Hayik S, Roitberg A, Seabra G, Kolossvai I, Wong KF, Paesani F, Vanicek J, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye Q, Wang J, Hsieh M-J, Cui G, Roe DR, Mathews DH, Seetin MG, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA (2010) AMBER 11. University of California, San FranciscoGoogle Scholar
  27. 27.
    Jakalian A, Bush BL, Jack DB, Bayly CI (2000) J Comput Chem 21:132–146CrossRefGoogle Scholar
  28. 28.
    Jakalian A, Jack DB, Bayly CI (2002) J Comput Chem 23:1623–1641CrossRefGoogle Scholar
  29. 29.
    Bayly CI, Cieplak P, Cornell WD, Kollman PA (1993) J Phys Chem 97:10269–10280CrossRefGoogle Scholar
  30. 30.
    Besler BH, Merz KM, Kollman PA (1990) J Comput Chem 11:431–439CrossRefGoogle Scholar
  31. 31.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, revision A02. Gaussian Inc, Wallingford CTGoogle Scholar
  32. 32.
    Ryckaert JP, Ciccotti G, Berendsen HJC (1977) J Comput Phys 23:327–341CrossRefGoogle Scholar
  33. 33.
    Berendsen HJC, Postma JPM, Van Gunsteren WF, Dinola A, Haak JR (1984) J Chem Phys 81:3684–3690CrossRefGoogle Scholar
  34. 34.
    Darden T, York D, Pedersen L (1993) J Chem Phys 98:10089–10092CrossRefGoogle Scholar
  35. 35.
    Genheden S, Ryde U (2011) J Comput Chem 32:187CrossRefGoogle Scholar
  36. 36.
    Wu X, Brooks BR (2003) Chem Phys Lett 381:512–518CrossRefGoogle Scholar
  37. 37.
    Tembe BL, McCammon JA (1984) Comp Chem 8:281–283CrossRefGoogle Scholar
  38. 38.
    Bennett CH (1976) J Comput Phys 22:245–268CrossRefGoogle Scholar
  39. 39.
    Shirts MR, Pande VS (2005) J Chem Phys 122:144107CrossRefGoogle Scholar
  40. 40.
    Shirts MR, Chodera JD (2008) J Chem Phys 129:124105CrossRefGoogle Scholar
  41. 41.
    Kirkwood JG (1935) J Chem Phys 3:300–313CrossRefGoogle Scholar
  42. 42.
    Zwanzig RWJ (1954) Chem Phys 22:1420–1426CrossRefGoogle Scholar
  43. 43.
    Steinbrecher T, Mobley DL, Case DA (2007) J Chem Phys 127:214108CrossRefGoogle Scholar
  44. 44.
    Ahlrichs R, Bär M, Häser M, Horn H, Kölmel C (1989) Chem Phys Lett 162:165CrossRefGoogle Scholar
  45. 45.
    Treutler O, Ahlrichs RJ (1995) Chem Phys 102:346CrossRefGoogle Scholar
  46. 46.
    Tao J, Perdew JP, Staroverov VN, Scuseria GE (2003) Phys Rev Lett 91:146401CrossRefGoogle Scholar
  47. 47.
    Becke AD (1988) Phys Rev A 38:3098–3100CrossRefGoogle Scholar
  48. 48.
    Perdew JP (1986) Phys Rev B 33:8822–8824CrossRefGoogle Scholar
  49. 49.
    Schäfer A, Huber C, Ahlrichs R (1994) J Chem Phys 100:5829CrossRefGoogle Scholar
  50. 50.
    Weigend F, Ahlrichs R (2005) Phys Chem Chem Phys 7:3297–3305CrossRefGoogle Scholar
  51. 51.
    Weigend F, Furche F, Ahlrichs R (2003) J Chem Phys 119:12753CrossRefGoogle Scholar
  52. 52.
    Eichkorn K, Treutler O, Öhm H, Häser M, Ahlrichs R (1995) Chem Phys Lett 240:283–290CrossRefGoogle Scholar
  53. 53.
    Eichkorn K, Weigend F, Treutler O, Ahlrichs R (1997) Theor Chem Acc 97:119–126CrossRefGoogle Scholar
  54. 54.
    Sierka M, Hogekamp A, Ahlrichs R (2003) J Chem Phys 118:9136CrossRefGoogle Scholar
  55. 55.
    Grimme S, Ehrlich S, Goerigk L (2011) J Comput Chem 32:1456–1465CrossRefGoogle Scholar
  56. 56.
  57. 57.
    Klamt A, Schüürmann J (1993) J Chem Soc Perkin Trans 2:799–805CrossRefGoogle Scholar
  58. 58.
    Schäfer A, Klamt A, Sattel D, Lohrenz JCW, Eckert F (2000) Phys Chem Chem Phys 2:2187–2193CrossRefGoogle Scholar
  59. 59.
    Klamt A, Jonas V, Bürger T, Lohrenz JCW (1998) J Phys Chem 102:5074–5085CrossRefGoogle Scholar
  60. 60.
    Klamt A (1995) J Phys Chem 99:2224CrossRefGoogle Scholar
  61. 61.
    Eckert F, Klamt A (2002) AIChE J 48:369CrossRefGoogle Scholar
  62. 62.
    Eckert F, Klamt A (2010) COSMOtherm, version C30, release 1301. COSMOlogic GmbH & Co KG, LeverkusenGoogle Scholar
  63. 63.
    Jensen F (1999) Introduction to computational chemistry. Wiley, Chichester, pp 298–303Google Scholar
  64. 64.
    Kaukonen M, Söderhjelm P, Heimdal J, Ryde U (2008) J Chem Theory Comput 4:985CrossRefGoogle Scholar
  65. 65.
    Söderhjelm P, Husberg C, Strambi A, Olivucci M, Ryde U (2009) J Chem Theory Comput 5:649CrossRefGoogle Scholar
  66. 66.
    Hu L, Eliasson J, Heimdal J, Ryde U (2009) J Phys Chem A 113:11793CrossRefGoogle Scholar
  67. 67.
    Genheden S, Ryde U (2012) J Chem Theory Comput 8:1449CrossRefGoogle Scholar
  68. 68.
    Wesolowski T, Warshel A (1994) J Phys Chem 98:5183–5187CrossRefGoogle Scholar
  69. 69.
    Olsson MH, Hong G, Warshel A (2003) J Am Chem Soc 125:5025–5039CrossRefGoogle Scholar
  70. 70.
    Wood RH, Yezdimer EM, Sakane S, Barriocanal JA, Doren DJJ (1999) Chem Phys 110:1329CrossRefGoogle Scholar
  71. 71.
    Rod TH, Ryde U (2005) Phys Rev Lett 94:138302CrossRefGoogle Scholar
  72. 72.
    Plotnikov NV, Kamerlin SCL, Warshel A (2011) J Phys Chem B 115:7950–7962CrossRefGoogle Scholar
  73. 73.
    Woods CJ, Manby FR, Mulholland AJ (2008) J Chem Phys 128:014109CrossRefGoogle Scholar
  74. 74.
    Beierlein FR, Michel J, Essex JW (2011) J Phys Chem B 115:4911–4926CrossRefGoogle Scholar
  75. 75.
    König G, Boresch S (2011) J Comput Chem 32:1082CrossRefGoogle Scholar
  76. 76.
    Dunning TH (1989) J Chem Phys 90:1007CrossRefGoogle Scholar
  77. 77.
    Woon DE, Dunning TH (1993) J Chem Phys 98:1358CrossRefGoogle Scholar
  78. 78.
    Polly R, Werner H-J, Manby FR, Knowles PJ (2004) Mol Phys 102:2311CrossRefGoogle Scholar
  79. 79.
    Werner H-J, Manby FR, Knowles PJ (2003) J Chem Phys 118:8149CrossRefGoogle Scholar
  80. 80.
    Weigend F (2002) Phys Chem Chem Phys 4:4285CrossRefGoogle Scholar
  81. 81.
    Weigend F, Köhn A, Hättig C (2002) J Chem Phys 116:3175CrossRefGoogle Scholar
  82. 82.
    Pipek J, Mezey PG (1989) J Chem Phys 90:4916–4926CrossRefGoogle Scholar
  83. 83.
    Mata RA, Werner H-J (2007) Mol Phys 105:2753–2761CrossRefGoogle Scholar
  84. 84.
    Dieterich JM, Werner H-J, Mata RA, Metz S, Thiel W (2010) J Chem Phys 132:035101CrossRefGoogle Scholar
  85. 85.
    Helgaker T, Klopper W, Koch H, Noga J (1997) J Chem Phys 106:9639CrossRefGoogle Scholar
  86. 86.
    Genheden S, Ryde U (2010) J Comput Chem 31:837–846Google Scholar
  87. 87.
    Pearlman DA, Charifson PS (2001) J Med Chem 44:3417CrossRefGoogle Scholar
  88. 88.
    Mikulskis P, Genheden S, Rydberg P, Sandberg L, Olsen L, Ryde U (2012) J Comput-Aided Mol Design 26:527–554CrossRefGoogle Scholar
  89. 89.
    Gibb CLD, Gibb B (2013) J Comput-Aided Mol Design. doi: 10.1007/s10822-013-9690-2
  90. 90.
    Heimdal J, Ryde U (2012) Phys Chem Chem Phys 14:12592–12604CrossRefGoogle Scholar
  91. 91.
    Genheden S, Nilsson I, Ryde U (2011) J Chem Inf Model 51:947–958CrossRefGoogle Scholar
  92. 92.
    Grimme S (2006) J Comput Chem 27:1787–1799CrossRefGoogle Scholar
  93. 93.
    Ryde U, Mata RA, Grimme S (2011) Dalton Trans 40:11176CrossRefGoogle Scholar
  94. 94.
    Sure R, Antony J, Grimme S (2014) J Phys Chem B (submitted)Google Scholar
  95. 95.
    Sure R, Grimme S (2013) J Comput Chem 34:1672–1685CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Paulius Mikulskis
    • 1
  • Daniela Cioloboc
    • 1
  • Milica Andrejić
    • 2
  • Sakshi Khare
    • 1
  • Joakim Brorsson
    • 1
  • Samuel Genheden
    • 3
  • Ricardo A. Mata
    • 2
  • Pär Söderhjelm
    • 1
    Email author
  • Ulf Ryde
    • 1
    Email author
  1. 1.Department of Theoretical Chemistry, Chemical CentreLund UniversityLundSweden
  2. 2.Institut für Physikalische ChemieUniversität GöttingenGöttingenGermany
  3. 3.School of ChemistryUniversity of SouthamptonSouthamptonUK

Personalised recommendations