Skip to main content
Log in

The SAMPL5 host–guest challenge: computing binding free energies and enthalpies from explicit solvent simulations by the attach-pull-release (APR) method

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

The absolute binding free energies and binding enthalpies of twelve host–guest systems in the SAMPL5 blind challenge were computed using our attach-pull-release (APR) approach. This method has previously shown good correlations between experimental and calculated binding data in retrospective studies of cucurbit[7]uril (CB7) and β-cyclodextrin (βCD) systems. In the present work, the computed binding free energies for host octa acid (OA or OAH) and tetra-endo-methyl octa-acid (TEMOA or OAMe) with guests are in good agreement with prospective experimental data, with a coefficient of determination (R2) of 0.8 and root-mean-squared error of 1.7 kcal/mol using the TIP3P water model. The binding enthalpy calculations achieve moderate correlations, with R2 of 0.5 and RMSE of 2.5 kcal/mol, for TIP3P water. Calculations using the newly developed OPC water model also show good performance. Furthermore, the present calculations semi-quantitatively capture the experimental trend of enthalpy-entropy compensation observed, and successfully predict guests with the strongest and weakest binding affinity. The most populated binding poses of all twelve systems, based on clustering analysis of 750 ns molecular dynamics (MD) trajectories, were extracted and analyzed. Computational methods using MD simulations and explicit solvent models in a rigorous statistical thermodynamic framework, like APR, can generate reasonable predictions of binding thermodynamics. Especially with continuing improvement in simulation force fields, such methods hold the promise of making substantial contributions to hit identification and lead optimization in the drug discovery process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Durrant JD, McCammon JA (2011) Molecular dynamics simulations and drug discovery. BMC Biol 9:71. doi:10.1186/1741-7007-9-71

    Article  CAS  Google Scholar 

  2. Deng Y, Roux B (2009) Computations of standard binding free energies with molecular dynamics simulations. J Phys Chem B 113:2234–2246. doi:10.1021/jp807701h

    Article  CAS  Google Scholar 

  3. Wang L, Wu Y, Deng Y, Kim B, Pierce L, Krilov G, Lupyan D, Robinson S, Dahlgren MK, Greenwood J, Romero DL (2015) Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field. J Am Chem Soc 137:2695–2703. doi:10.1021/ja512751q

    Article  CAS  Google Scholar 

  4. Yallapu MM, Jaggi M, Chauhan SC (2010) Poly(beta-cyclodextrin)/Curcumin Self-Assembly: a novel approach to improve curcumin delivery and its therapeutic efficacy in prostate cancer cells. Macromol Biosci 10:1141–1151. doi:10.1002/mabi.201000084

    Article  CAS  Google Scholar 

  5. Hamasaki K, Ikeda H, Nakamura A, Ueno A, Toda F, Suzuki I, Osa T (1993) Fluorescent sensors of molecular recognition. Modified cyclodextrins capable of exhibiting guest-responsive twisted intramolecular charge transfer fluorescence. J Am Chem Soc 115:5035–5040. doi:10.1021/ja00065a012

    Article  CAS  Google Scholar 

  6. Zhang B, Isaacs L (2014) Acyclic cucurbit[n]uril-type molecular containers: influence of aromatic walls on their function as solubilizing excipients for insoluble drugs. J Med Chem 57:9554–9563. doi:10.1021/jm501276u

    Article  CAS  Google Scholar 

  7. Geballe MT, Skillman AG, Nicholls A, Guthrie JP, Taylor PJ (2010) The SAMPL2 blind prediction challenge: introduction and overview. J Comput Aided Mol Des 24:259–279. doi:10.1007/s10822-010-9350-8

    Article  CAS  Google Scholar 

  8. Muddana HS, Varnado CD, Bielawski CW, Urbach AR, Isaacs L, Geballe MT, Gilson MK (2012) Blind prediction of host-guest binding affinities: a new SAMPL3 challenge. J Comput Aided Mol Des 26:475–487. doi:10.1007/s10822-012-9554-1

    Article  CAS  Google Scholar 

  9. Muddana HS, Fenley AT, Mobley DL, Gilson MK (2014) The SAMPL4 host-guest blind prediction challenge: an overview. J Comput Aided Mol Des 28:305–317. doi:10.1007/s10822-014-9735-1

    Article  CAS  Google Scholar 

  10. Mobley DL, Wymer KL, Lim NM, Guthrie JP (2014) Blind prediction of solvation free energies from the SAMPL4 challenge. J Comput Aided Mol Des 28:135–150. doi:10.1007/s10822-014-9718-2

    Article  CAS  Google Scholar 

  11. Fenley AT, Henriksen NM, Muddana HS, Gilson MK (2014) Bridging calorimetry and simulation through precise calculations of cucurbituril-guest binding enthalpies. J Chem Theory Comput 10:4069–4078

    Article  CAS  Google Scholar 

  12. Gibb CLD, Gibb BC (2014) Binding of cyclic carboxylates to octa-acid deep-cavity cavitand. J Comput Aided Mol Des 28:319–325. doi:10.1007/s10822-013-9690-2

    Article  CAS  Google Scholar 

  13. Gan H, Benjamin CJ, Gibb BC (2011) Nonmonotonic assembly of a deep-cavity cavitand. J Am Chem Soc 133:4770–4773. doi:10.1021/ja200633d

    Article  CAS  Google Scholar 

  14. Gan H, Gibb BC (2013) Guest-mediated switching of the assembly state of a water-soluble deep-cavity cavitand. Chem Commun 49:1395–1397. doi:10.1039/c2cc38227j

    Article  CAS  Google Scholar 

  15. Jordan JH, Gibb BC (2014) Molecular containers assembled through the hydrophobic effect. Chem Soc Rev 44:547–585. doi:10.1039/c4cs00191e

    Article  Google Scholar 

  16. Henriksen NM, Fenley AT, Gilson MK (2015) Computational Calorimetry: high-precision calculation of host-guest binding thermodynamics. J Chem Theory Comput 11:4377–4394. doi:10.1021/acs.jctc.5b00405

    Article  CAS  Google Scholar 

  17. Izadi S, Anandakrishnan R, Onufriev AV (2014) Building water models: a different approach. J Phys Chem Lett 5:3863–3871. doi:10.1021/jz501780a

    Article  CAS  Google Scholar 

  18. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25:1157–1174. doi:10.1002/jcc.20035

    Google Scholar 

  19. 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 AP, Bloino J, Zheng G, Sonnenberg JL, Had M, Fox DJ (2013) Gaussian 09, Revision D.01. Gaussian Inc, Wallingford. doi:10.1017/CBO9781107415324.004

    Google Scholar 

  20. Singh UC, Kollman PA (1984) An approach to computing electrostatic charges for molecules. J Comput Chem 5:129–145. doi:10.1002/jcc.540050204

    Article  CAS  Google Scholar 

  21. Besler BH, Merz KM, Kollman PA (1990) Atomic charges derived from semiempirical methods. J Comput Chem 11:431–439. doi:10.1002/jcc.540110404

    Article  CAS  Google Scholar 

  22. Molecular Operating Environment (MOE) 2013.08 (2016) Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7

  23. Joung IS, Cheatham TE (2008) Determination of alkali and halide monovalent ion parameters for use in explicitly solvated biomolecular simulations. J Phys Chem B 112:9020–9041. doi:10.1021/jp8001614

    Article  CAS  Google Scholar 

  24. Shirts MR, Klein C, Swails JM, Yin J, Gilson MK, Mobley DL, Case DA, Zhong ED (2016) Lessons learned from comparing molecular dynamics engines on the SAMPL5 dataset. J Comput Aided Mol Des. doi:10.1007/s10822-016-9977-1

  25. Kirkwood JG (1935) Statistical Mechanics of Fluid Mixtures. J Chem Phys 3:300–313. doi:10.1063/1.1749657

    Article  CAS  Google Scholar 

  26. Velez-Vega C, Gilson MK (2012) Force and stress along simulated dissociation pathways of cucurbituril-guest systems. J Chem Theory Comput 8:966–976. doi:10.1021/ct2006902

    Article  CAS  Google Scholar 

  27. Case DA, Babin V, Berryman JT, Betz RM, Cai Q, Cerutti DS, Cheatham III TE, Darden TA, Duke RE, Gohlke H, Goetz AW, Gusarov S, Homeyer N, Janowski P, Kaus J, Kolossváry I, Kovalenko A, Lee TS, LeGrand S, Luchko T, Luo R, Madej B, Merz KM, Paesani F, Roe DR, Roitberg A, Sagui C, Salomon-Ferrer R, Seabra G, Simmerling CL, Smith W, Swails J, Walker RC, Wang J, Wolf RM, Wu X, Kollman PA (2014) AMBER 14. University of California, San Francisco

  28. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935. doi:10.1063/1.445869

    Article  CAS  Google Scholar 

  29. Case DA, Betz, RM, Botello-Smith W, Cerutti, DS, Cheatham III TE, Darden, TA, Duke RE, Giese TJ, Gohlke H, Goetz AW, Homeyer N, Izadi S, Janowski P, Kaus J, Kovalenko A, Lee TS, LeGrand S, Li P, Lin C, Luchko T, Luo R, Madej B, Mermelstein D, Merz KM, Monard G, Nguyen H, Nguyen HT, Omelyan I, Onufriev A, Roe DR, Roitberg A, Sagui C, Simmerling CL, Swails J, Walker RC, Wang J, Wolf RM, Wu X, Xiao L, York DM, Kollman PA (2016) AMBER 16, University of California, San Francisco

  30. Berendsen HJ, Postma JV, van Gunsteren WF, DiNola AR, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690. doi:10.1063/1.448118

    Article  CAS  Google Scholar 

  31. Loncharich RJ, Brooks BR, Pastor RW (1992) Langevin dynamics of peptides: the frictional dependence of isomerization rates of N-acetylalanyl-N’-methylamide. Biopolymers 32:523–535. doi:10.1002/bip.360320508

    Article  CAS  Google Scholar 

  32. Shirts MR, Mobley DL, Chodera JD, Pande VS (2007) Accurate and efficient corrections for missing dispersion interactions in molecular simulations. J Phys Chem B 111:13052–13063. doi:10.1021/jp0735987

    Article  CAS  Google Scholar 

  33. Wu X, Brooks BR (2005) Isotropic periodic sum: a method for the calculation of long-range interactions. J Chem Phys. doi:10.1063/1.1836733

    Google Scholar 

  34. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N log(N) method for Ewald sums in large systems. J Chem Phys 98:10089. doi:10.1063/1.464397

    Article  CAS  Google Scholar 

  35. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593. doi:10.1063/1.470117

    Article  CAS  Google Scholar 

  36. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341. doi:10.1016/0021-9991(77)90098-5

    Article  CAS  Google Scholar 

  37. Miyamoto S, Kollman PA (1992) SETTLE: an analytical version of the SHAKE and RATTLE algorithm for rigid water models. J Comput Chem 13:952–962. doi:10.1002/jcc.540130805

    Article  CAS  Google Scholar 

  38. Sullivan MR, Sokkalingam P, Nguyen T, Donahue JP, Gibb BC (2016) Binding of carboxylate and trimethylammonium salts to octa-acid and TEMOA deep-cavity cavitands. J Comput Aided Mol Des. doi:10.1007/s10822-016-9925-0

    Google Scholar 

  39. Yin J, Henriksen NM, Slochower DR, Shirts MR, Chiu MW, Mobley DL, Gilson MK (2016) Overview of the SAMPL5 host-guest challenge: are we doing better? J Comput Aided Mol Des (in press)

  40. Flyvbjerg H, Petersen HG (1989) Error estimates on averages of correlated data. J Chem Phys 91:461–466. doi:10.1063/1.457480

    Article  CAS  Google Scholar 

  41. Mikulskis P, Cioloboc D, Andrejić M, Khare S, Brorsson J, Genheden S, Mata RA, Söderhjelm P, Ryde U (2014) Free-energy perturbation and quantum mechanical study of SAMPL4 octa-acid host-guest binding energies. J Comput Aided Mol Des 28:375–400. doi:10.1007/s10822-014-9739-x

    Article  CAS  Google Scholar 

  42. Bosisio S, Mey ASJS, Michel J (2016) Blinded predictions of host-guest standard free energies of binding in the SAMPL5 challenge. J Comput Aided Mol Des. doi:10.1007/s10822-016-9933-0

    Google Scholar 

  43. Woods CJW, Mey A, Calabro G, Michel J (2016) Sire Molecular Simulations Framework. http://siremol.org. Accessed July 28th

  44. Eastman P, Friedrichs MS, Chodera JD, Radmer RJ, Bruns CM, Ku JP, Beauchamp KA, Lane TJ, Wang LP, Shukla D, Tye T (2013) OpenMM 4: a reusable, extensible, hardware independent library for high performance molecular simulation. J Chem Theory Comput 9:461–469. doi:10.1021/ct300857j

    Article  CAS  Google Scholar 

  45. Gilson MK, Given JA, Bush BL, McCammon JA (1997) The statistical-thermodynamic basis for computation of binding affinities: a critical review. Biophys J 72:1047–1069. doi:10.1016/S0006-3495(97)78756-3

    Article  CAS  Google Scholar 

  46. Boresch S, Tettinger F, Leitgeb M, Karplus M (2003) Absolute binding free energies: a quantitative approach for their calculation. J Phys Chem B 107:9535–9551. doi:10.1021/jp0217839

    Article  CAS  Google Scholar 

  47. Shirts MR, Chodera JD (2008) Statistically optimal analysis of samples from multiple equilibrium states. J Chem Phys 129:124105. doi:10.1063/1.2978177

    Article  Google Scholar 

  48. Gao K, Yin J, Henriksen NM, Fenley AT, Gilson MK (2015) Binding enthalpy calculations for a neutral host-guest pair yield widely divergent salt effects across water models. J Chem Theory Comput Chem theory Comput 11:4555–4564. doi:10.1021/acs.jctc.5b00676

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This article was made possible in part by NIH grants R01GM061300 and U01GM111528, and by Air Force Office of Scientific Research (AFOSR) Basic Research Initiative (BRI) grant (FA9550-12-1-644 0414). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or AFOSR. MKG has an equity interest in and is a cofounder and scientific advisor of VeraChem LLC. We thank Prof. Bruce Gibb for providing the octa-acid experimental data for SAMPL5.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael K. Gilson.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 329 kb)

Supplementary material 2 (RAR 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yin, J., Henriksen, N.M., Slochower, D.R. et al. The SAMPL5 host–guest challenge: computing binding free energies and enthalpies from explicit solvent simulations by the attach-pull-release (APR) method. J Comput Aided Mol Des 31, 133–145 (2017). https://doi.org/10.1007/s10822-016-9970-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-016-9970-8

Keywords

Navigation