Skip to main content
Springer Nature Link
Log in

Predictions of hydration free energies from continuum solvent with solute polarizable models: the SAMPL2 blind challenge

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

Abstract

This paper reports the results of our attempt to predict hydration free energies on the SAMPL2 blind challenge dataset. We mostly examine the effects of the solute electrostatic component on the accuracy of the predictions. The usefulness of electronic polarization in predicting hydration free energies is assessed by comparing the Electronic Polarization from Internal Continuum model and the self consistent reaction field IEF-PCM to standard non-polarizable charge models such as RESP and AM1-BCC. We also determine an optimal restraint weight for Dielectric-RESP atomic charges fitting. Statistical analysis of the results could not distinguish the methods from one another. The smallest average unsigned error obtained is 1.9 ± 0.6 kcal/mol (95% confidence level). A class of outliers led us to investigate the importance of the solute–solvent instantaneous induction energy, a missing term in PB continuum models. We estimated values between −1.5 and −6 kcal/mol for a series of halo-benzenes which can explain why some predicted hydration energies of non-polar molecules significantly disagreed with experiment.

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

Access this article

Log in via an institution

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Overview paper SAMPL2 referenceGuthrie, J. P. JCAM. 2010

  2. Michel J, Tirado-Rives J, Jorgensen WL (2009) Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization. J Am Chem Soc 131:15403–15411

    Article  CAS  Google Scholar 

  3. Guthrie JP (2009) A blind challenge for computational solvation free energies: introduction and overview. J Phys Chem B 113:4501–4507

    Article  CAS  Google Scholar 

  4. Honig B, Nicholls A (1995) Classical electrostatics in biology and chemistry. Science 268:1144–1149

    Article  CAS  Google Scholar 

  5. Jeancharles A, Nicholls A, Sharp K, Honig B, Tempczyk A, Hendrickson TF, Still WC (1991) Electrostatic contributions to solvation energies—comparison of free-energy perturbation and continuum calculations. J Am Chem Soc 113:1454–1455

    Article  CAS  Google Scholar 

  6. Sharp K, Jean-Charles A, Honig B (1992) A local dielectric-constant model for solvation free-energies which accounts for solute polarizability. J Phys Chem 96:3822–3828

    Article  CAS  Google Scholar 

  7. Sitkoff D, Sharp KA, Honig B (1994) Accurate calculation of hydration free-energies using macroscopic solvent models. J Phys Chem 98:1978–1988

    Article  CAS  Google Scholar 

  8. Feig M, Onufriev A, Lee MS, Im W, Case DA, Brooks CL (2004) Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures. J Comput Chem 25:265–284

    Article  CAS  Google Scholar 

  9. Nicholls A, Wlodek S, Grant JA (2009) The SAMP1 solvation challenge: further lessons regarding the pitfalls of parametrization. J Phys Chem B 113:4521–4532

    Article  CAS  Google Scholar 

  10. Nina M, Beglov D, Roux B (1997) Atomic radii for continuum electrostatics calculations based on molecular dynamics free energy simulations. J Phys Chem B 101:5239–5248

    Article  CAS  Google Scholar 

  11. Nicholls A, Mobley DL, Guthrie JP, Chodera JD, Bayly CI, Cooper MD, Pande VS (2008) Predicting small-molecule solvation free energies: an informal blind test for computational chemistry. J Med Chem 51:769–779

    Article  CAS  Google Scholar 

  12. Shivakumar D, Deng YQ, Roux B (2009) Computations of absolute solvation free energies of small molecules using explicit and implicit solvent model. J Chem Theory Comput 5:919–930

    Article  CAS  Google Scholar 

  13. Truchon J-F, Nicholls A, Roux B, Iftimie RI, Bayly CI (2009) Integrated continuum dielectric approaches to treat molecular polarizability and the condensed phase: refractive index and implicit solvation. J Chem Theory Comput 5:1785–1802

    Article  CAS  Google Scholar 

  14. OpenEye Scientific Software Inc (2007) Zap Toolkit, version 2.2.1; Santa Fe, NM, USA

  15. Grant JA, Pickup BT, Nicholls A (2001) A smooth permittivity function for Poisson-Boltzmann solvation methods. J Comput Chem 22:608–640

    Article  CAS  Google Scholar 

  16. Tan YH, Luo R (2007) Continuum treatment of electronic polarization effect. J Chem Phys 126:094103

    Article  CAS  Google Scholar 

  17. Naim M, Bhat S, Rankin KN, Dennis S, Chowdhury SF, Siddiqi I, Drabik P, Sulea T, Bayly CI, Jakalian A, Purisima EO (2007) Solvated interaction energy (SIE) for scoring protein-ligand binding affinities. 1. Exploring the parameter space. J Chem Inf Model 47:122–133

    Article  CAS  Google Scholar 

  18. Rankin KN, Sulea T, Purisima EO (2003) On the transferability of hydration-parametrized continuum electrostatics models to solvated binding calculations. J Comput Chem 24:954–962

    Article  CAS  Google Scholar 

  19. Warshel A, Sharma PK, Kato M, Parson WW (2006) Modeling electrostatic effects in proteins. Biochimica et Biophysica Acta-Proteins Proteomics 1764:1647–1676

    Article  CAS  Google Scholar 

  20. Schnieders MJ, Baker NA, Ren P, Ponder JW (2007) Polarizable atomic multipole solutes in a Poisson-Boltzmann continuum. J Chem Phys 126:124114

    Article  CAS  Google Scholar 

  21. Weininger D (1990) Smiles.3. Depict—graphical depiction of chemical structures. J Chem Inf Model 30:237–243

    Article  CAS  Google Scholar 

  22. Weininger D, Weininger A, Weininger JL (1989) Smiles.2. Algorithm for generation of unique smiles notation. J Chem Inf Model 29:97–101

    Article  CAS  Google Scholar 

  23. Weininger D (1988) Smiles, a chemical language and information-system.1. Introduction to methodology and encoding rules. J Chem Inf Model 28:31–36

    Article  CAS  Google Scholar 

  24. OpenEye Scientific Software Inc (2007) OMEGA, version 2.2.1; Santa Fe, NM, USA

  25. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery Jr JA, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Menucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2004) Gaussian 03, Revision, version C.02; Wallingford CT, USA

  26. Becke AD (1993) Density-functional thermochemistry.3. The role of exact exchange. J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  27. Becke AD (1993) A new mixing of Hartree-Fock and local density-functional theories. J Chem Phys 98:1372–1377

    Article  CAS  Google Scholar 

  28. Becke AD (1988) Density-functional exchange-energy approximation with correct asymptotic-behavior. Phys Rev A 38:3098–3100

    Article  CAS  Google Scholar 

  29. Jakalian A, Jack DB, Bayly CI (2002) Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation. J Comput Chem 23:1623–1641

    Article  CAS  Google Scholar 

  30. Jakalian A, Bush BL, Jack DB, Bayly CI (2000) Fast, efficient generation of high-quality atomic Charges. AM1-BCC model: I. Method. J Comput Chem 21:132–146

    Article  CAS  Google Scholar 

  31. Singh UC, Kollman PA (1984) An approach to computing electrostatic charges for molecules. J Comput Chem 5:129–145

    Article  CAS  Google Scholar 

  32. Truchon J-F, Nicholls A, Grant JA, Iftimie RI, Roux B, Bayly CI (2009) Extending the polarizable continuum dielectric model to account for electronic polarization in intermolecular interactions. J Comput Chem 31:811–824

    Google Scholar 

  33. Bayly CI, Cieplak P, Cornell WD, Kollman PA (1993) A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges—the resp model. J Phys Chem 97:10269–10280

    Article  CAS  Google Scholar 

  34. The restraints are in a.u. and correspond to the a parameter in equation 10 of reference 33. 2009

  35. Bush BL, Bayly CI, Halgren TA (1999) Consensus bond-charge increments fitted to electrostatic potential or field of many compounds: application to MMFF94 training set. J Comput Chem 20:1495–1516

    Article  CAS  Google Scholar 

  36. Woon DE, Dunning J (1993) Gaussian basis sets for use in correlated molecular calculations. III. The atoms aluminum through argon. J Chem Phys 98:1358–1371

    Article  CAS  Google Scholar 

  37. Mennucci B, Cances E, Tomasi J (1997) Evaluation of solvent effects in isotropic and anisotropic dielectrics and in ionic solutions with a unified integral equation method: theoretical bases, computational implementation, and numerical applications. J Phys Chem B 101:10506–10517

    Article  CAS  Google Scholar 

  38. Cances E, Mennucci B, Tomasi J (1997) A new integral equation formalism for the polarizable continuum model: theoretical background and applications to isotropic and anisotropic dielectrics. J Chem Phys 107:3032–3041

    Article  CAS  Google Scholar 

  39. Mennucci B, Tomasi J (1997) Continuum solvation models: a new approach to the problem of solute’s charge distribution and cavity boundaries. J Chem Phys 106:5151–5158

    Article  CAS  Google Scholar 

  40. Truchon J-F (2008) Modéliser la polarisation électronique par un continuum diélectrique intramoléculaire: Vers un champ de force polarisable pour la chimie bioorganique. Ph.D. Université de Montréal

  41. Halgren TA (1999) MMFF VI. MMFF94 s option for energy minimization studies. J Comput Chem 20:720–729

    Article  CAS  Google Scholar 

  42. Halgren TA (1999) MMFF VII. Characterization of MMFF94, MMFF94 s, and other widely available force fields for conformational energies and for intermolecular-interaction energies and geometries. J Comput Chem 20:730–748

    Article  CAS  Google Scholar 

  43. Halgren TA (1996) Merck molecular force field.1. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem 17:490–519

    Article  CAS  Google Scholar 

  44. Halgren TA (1992) Representation of Vanderwaals (Vdw) interactions in molecular mechanics force-fields—potential form, combination rules, and Vdw parameters. J Am Chem Soc 114:7827–7843

    Article  CAS  Google Scholar 

  45. Bondi A (1964) van der Waals volumes and radii. J Phys Chem 68:441–451

    Article  CAS  Google Scholar 

  46. 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

    Article  CAS  Google Scholar 

  47. Wang JM, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25:1157–1174

    Article  CAS  Google Scholar 

  48. Private communication with Dr. Christopher Bayly 2009

  49. Rizzo RC, Aynechi T, Case DA, Kuntz ID (2006) Estimation of absolute free energies of hydration using continuum methods: accuracy of partial, charge models and optimization of nonpolar contributions. J Chem Theory Comput 2:128–139

    Article  CAS  Google Scholar 

  50. Mobley DL, Dill KA, Chodera JD (2008) Treating entropy and conformational changes in implicit solvent simulations of small molecules. J Phys Chem B 112:938–946

    Article  CAS  Google Scholar 

  51. Nicholls A (2007) OpenEye CUP8 conference, Santa FE, NM, February 26–28, 2007

Download references

Acknowledgments

The authors thank Dr. Christopher Bayly from Merck Frosst Canada for his guidance on the 3-stage RESP procedure, for the informatics tools he gratefully provided to us and for his comments on the manuscript.

Author information

Authors and Affiliations

  1. Merck Frosst Canada, 16711, TransCanada Hwy, Kirkland, QC, H9H 3L1, Canada

    Alexandre Meunier & Jean-François Truchon

Authors
  1. Alexandre Meunier
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Jean-François Truchon
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Jean-François Truchon.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLS 123 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meunier, A., Truchon, JF. Predictions of hydration free energies from continuum solvent with solute polarizable models: the SAMPL2 blind challenge. J Comput Aided Mol Des 24, 361–372 (2010). https://doi.org/10.1007/s10822-010-9339-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-010-9339-3

Keywords