Journal of Computer-Aided Molecular Design

, Volume 28, Issue 3, pp 277–287 | Cite as

The SAMPL4 hydration challenge: evaluation of partial charge sets with explicit-water molecular dynamics simulations

  • Hari S. Muddana
  • Neil V. Sapra
  • Andrew T. Fenley
  • Michael K. Gilson


We used blind predictions of the 47 hydration free energies in the SAMPL4 challenge to test multiple partial charge models in the context of explicit solvent free energy simulations with the general AMBER force field. One of the partial charge models, IPolQ-Mod, is a fast continuum solvent-based implementation of the IPolQ approach. The AM1-BCC, restrained electrostatic potential (RESP) and IpolQ-Mod approaches all perform reasonably well (R2 > 0.8), while VCharge, though faster, gives less accurate results (R2 of 0.5). The AM1-BCC results are more accurate than those of RESP for tertiary amines and nitrates, but the overall difference in accuracy between these methods is not statistically significant. Interestingly, the IPolQ-Mod method is found to yield partial charges in very close agreement with RESP. This observation suggests that the success of RESP may be attributed to its fortuitously approximating the arguably more rigorous IPolQ approach.


SAMPL4 Hydration Partial charge IPolQ RESP AM1-BCC VCharge 



The authors thank David Mobley, Karisa Wymer, and Christopher Fennell, for providing their data for additional analysis in this paper. This study was made possible in part by grant GM61300 from the NIGMS. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. MKG is a founder of and has an equity interest in VeraChem LLC. Although grant GM61300 has been identified for conflict of interest management, the research findings included in this particular publication may not necessarily relate to the interests of VeraChem LLC. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.


  1. 1.
    Levy Y, Onuchic JN (2006) Water mediation in protein folding and molecular recognition. Annu Rev Bioph Biom 35:389–415CrossRefGoogle Scholar
  2. 2.
    Kauzmann W (1959) Some factors in the interpretation of protein denaturation. Adv Protein Chem 14:1–63CrossRefGoogle Scholar
  3. 3.
    Tanford C (1962) Contribution of hydrophobic interactions to stability of globular conformation of proteins. J Am Chem Soc 84(22):4240CrossRefGoogle Scholar
  4. 4.
    Lockhart DJ, Kim PS (1993) Electrostatic screening of charge and dipole interactions with the helix backbone. Science 260(5105):198–202CrossRefGoogle Scholar
  5. 5.
    Tan CH, Yang LJ, Luo R (2006) How well does Poisson-Boltzmann implicit solvent agree with explicit solvent? A quantitative analysis. J Phys Chem B 110(37):18680–18687CrossRefGoogle Scholar
  6. 6.
    Ladbury JE (1996) Just add water! The effect of water on the specificity of protein-ligand binding sites and its potential application to drug design. Chem Biol 3(12):973–980CrossRefGoogle Scholar
  7. 7.
    Nicholls A, Honig B (1991) A rapid finite-difference algorithm, utilizing successive over-relaxation to solve the Poisson-Boltzmann equation. J Comput Chem 12(4):435–445CrossRefGoogle Scholar
  8. 8.
    Gilson MK, Sharp KA, Honig BH (1988) Calculating the electrostatic potential of molecules in solution—method and error assessment. J Comput Chem 9(4):327–335CrossRefGoogle Scholar
  9. 9.
    Im W, Beglov D, Roux B (1998) Continuum solvation model: computation of electrostatic forces from numerical solutions to the Poisson-Boltzmann equation. Comput Phys Commun 111(1–3):59–75CrossRefGoogle Scholar
  10. 10.
    Still WC, Tempczyk A, Hawley RC, Hendrickson T (1990) Semianalytical treatment of solvation for molecular mechanics and dynamics. J Am Chem Soc 112(16):6127–6129CrossRefGoogle Scholar
  11. 11.
    Onufriev A, Bashford D, Case DA (2000) Modification of the generalized born model suitable for macromolecules. J Phys Chem B 104(15):3712–3720CrossRefGoogle Scholar
  12. 12.
    Lee MS, Salsbury FR, Brooks CL (2002) Novel generalized born methods. J Chem Phys 116(24):10606–10614CrossRefGoogle Scholar
  13. 13.
    Sigalov G, Fenley A, Onufriev A (2006) Analytical electrostatics for biomolecules: beyond the generalized Born approximation. J Chem Phys 124(12):124902CrossRefGoogle Scholar
  14. 14.
    Gallicchio E, Paris K, Levy RM (2009) The AGBNP2 implicit solvation model. J Chem Theory Comput 5(9):2544–2564CrossRefGoogle Scholar
  15. 15.
    Warshel A (1979) Calculations of chemical processes in solutions. J Phys Chem-Us 83(12):1640–1652CrossRefGoogle Scholar
  16. 16.
    Kovalenko A, Hirata F (2000) Potentials of mean force of simple ions in ambient aqueous solution. I. Three-dimensional reference interaction site model approach. J Chem Phys 112(23):10391–10402CrossRefGoogle Scholar
  17. 17.
    Kovalenko A, Hirata F (2000) Potentials of mean force of simple ions in ambient aqueous solution. II. Solvation structure from the three-dimensional reference interaction site model approach, and comparison with simulations. J Chem Phys 112(23):10403–10417CrossRefGoogle Scholar
  18. 18.
    Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79(2):926–935CrossRefGoogle Scholar
  19. 19.
    Mobley DL, Bayly CI, Cooper MD, Shirts MR, Dill KA (2009) Small molecule hydration free energies in explicit solvent: an extensive test of fixed-charge atomistic simulations. J Chem Theory Comput 5(2):350–358CrossRefGoogle Scholar
  20. 20.
    Muddana HS, Gilson MK (2012) Prediction of SAMPL3 host-guest binding affinities: evaluating the accuracy of generalized force-fields. J Comput Aid Mol Des 26(5):517–525CrossRefGoogle Scholar
  21. 21.
    Halgren TA (1992) Representation of van der Waals (vdW) interactions in molecular mechanics force-fields—potential form, combination rules, and vdW parameters. J Am Chem Soc 114(20):7827–7843CrossRefGoogle Scholar
  22. 22.
    Kaminski GA, Stern HA, Berne BJ, Friesner RA, Cao YXX, Murphy RB, Zhou RH, Halgren TA (2002) Development of a polarizable force field for proteins via ab initio quantum chemistry: first generation model and gas phase tests. J Comput Chem 23(16):1515–1531CrossRefGoogle Scholar
  23. 23.
    Ponder JW, Wu CJ, Ren PY, Pande VS, Chodera JD, Schnieders MJ, Haque I, Mobley DL, Lambrecht DS, DiStasio RA, Head-Gordon M, Clark GNI, Johnson ME, Head-Gordon T (2010) Current status of the AMOEBA polarizable force field. J Phys Chem B 114(8):2549–2564CrossRefGoogle Scholar
  24. 24.
    Mobley DL, Dumont E, Chodera JD, Dill KA (2007) Comparison of charge models for fixed-charge force fields: small-molecule hydration free energies in explicit solvent. J Phys Chem B 111(9):2242–2254CrossRefGoogle Scholar
  25. 25.
    Guthrie JP (2009) A blind challenge for computational solvation free energies: introduction and overview. J Phys Chem B 113(14):4501–4507CrossRefGoogle Scholar
  26. 26.
    Geballe MT, Skillman AG, Nicholls A, Guthrie JP, Taylor PJ (2010) The SAMPL2 blind prediction challenge: introduction and overview. J Comput Aid Mol Des 24(4):259–279CrossRefGoogle Scholar
  27. 27.
    Geballe MT, Guthrie JP (2012) The SAMPL3 blind prediction challenge: transfer energy overview. J Comput Aid Mol Des 26(5):489–496CrossRefGoogle Scholar
  28. 28.
    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 Aid Mol Des 26(5):475–487CrossRefGoogle Scholar
  29. 29.
    Mobley DL, Wymer KL, Lim NM (2014) Blind prediction of solvation free energies from the SAMPL4 challenge. J Comput Aid Mol Des 24:357Google Scholar
  30. 30.
    Muddana HS, Fenley AT, Mobley DL, Gilson MK (2014) Blind prediction of the host-guest binding affinities from the SAMPL4 challenge. J Comput Aid Mol DesGoogle Scholar
  31. 31.
    Staudinger J, Roberts PV (1996) A critical review of Henry’s law constants for environmental applications. Crit Rev Environ Sci Tec 26(3):205–297CrossRefGoogle Scholar
  32. 32.
    Saxena P, Hildemann LM (1996) Water-soluble organics in atmospheric particles: a critical review of the literature and application of thermodynamics to identify candidate compounds. J Atmos Chem 24(1):57–109CrossRefGoogle Scholar
  33. 33.
    Suntio LR, Shiu WY, Mackay D, Seiber JN, Glotfelty D (1988) Critical-review of Henry Law constants for pesticides. Rev Environ Contam T 103:1–59Google Scholar
  34. 34.
    Wang JM, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25(9):1157–1174CrossRefGoogle Scholar
  35. 35.
    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-Us 97(40):10269–10280CrossRefGoogle Scholar
  36. 36.
    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(2):132–146CrossRefGoogle Scholar
  37. 37.
    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(16):1623–1641CrossRefGoogle Scholar
  38. 38.
    Gilson MK, Gilson HS, Potter MJ (2003) Fast assignment of accurate partial atomic charges: an electronegativity equalization method that accounts for alternate resonance forms. J Chem Inf Comput Sci 43(6):1982–1997CrossRefGoogle Scholar
  39. 39.
    Cerutti DS, Rice JE, Swope WC, Case DA (2013) Derivation of fixed partial charges for amino acids accommodating a specific water model and implicit polarization. J Phys Chem B 117(8):2328–2338CrossRefGoogle Scholar
  40. 40.
    Karamertzanis PG, Raiteri P, Galindo A (2010) The use of anisotropic potentials in modeling water and free energies of hydration. J Chem Theory Comput 6(5):1590–1607CrossRefGoogle Scholar
  41. 41.
    Fennell CJ, Wymer KL, Mobley DL (2014) Polarized alcohol in condensed-phase and its role in small molecule hydration. In preparationGoogle Scholar
  42. 42.
    Muddana HS, Sapra NV, Fenley AT, Gilson MK (2013) The electrostatic response of water to neutral polar solutes: implications for continuum solvent modeling. J Chem Phys 138(22):224504CrossRefGoogle Scholar
  43. 43.
    Beutler TC, Mark AE, Vanschaik RC, Gerber PR, van Gunsteren WF (1994) Avoiding singularities and numerical instabilities in free-energy calculations based on molecular simulations. Chem Phys Lett 222(6):529–539CrossRefGoogle Scholar
  44. 44.
    Bennett CH (1976) Efficient estimation of free-energy differences from Monte-Carlo data. J Comput Phys 22(2):245–268CrossRefGoogle Scholar
  45. 45.
    Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4(3):435–447CrossRefGoogle Scholar
  46. 46.
    Berendsen HJC, Postma JPM, van Gunsteren WF, Dinola A, Haak JR (1984) Molecular-dynamics with coupling to an external bath. J Chem Phys 81(8):3684–3690CrossRefGoogle Scholar
  47. 47.
    Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103(19):8577–8593CrossRefGoogle Scholar
  48. 48.
    Miyamoto S, Kollman PA (1992) Settle—an analytical version of the Shake and Rattle algorithm for rigid water models. J Comput Chem 13(8):952–962CrossRefGoogle Scholar
  49. 49.
    Wang JM, Wang W, Kollman PA, Case DA (2006) Automatic atom type and bond type perception in molecular mechanical calculations. J Mol Graph Model 25(2):247–260CrossRefGoogle Scholar
  50. 50.
    Mennucci B, Cammi R, Tomasi J (1998) Excited states and solvatochromic shifts within a nonequilibrium solvation approach: a new formulation of the integral equation formalism method at the self-consistent field, configuration interaction, and multiconfiguration self-consistent field level. J Chem Phys 109(7):2798–2807CrossRefGoogle Scholar
  51. 51.
    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(4):919–930CrossRefGoogle Scholar
  52. 52.
    Shivakumar D, Williams J, Wu YJ, Damm W, Shelley J, Sherman W (2010) Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput 6(5):1509–1519CrossRefGoogle Scholar
  53. 53.
    Jorgensen WL, Maxwell DS, TiradoRives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118(45):11225–11236CrossRefGoogle Scholar
  54. 54.
    Momany FA, Rone R (1992) Validation of the general-purpose Quanta(R)3.2/Charmm(R) force-field. J Comput Chem 13(7):888–900CrossRefGoogle Scholar
  55. 55.
    Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, Darian E, Guvench O, Lopes P, Vorobyov I, MacKerell AD (2010) CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem 31(4):671–690Google Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Hari S. Muddana
    • 1
  • Neil V. Sapra
    • 1
  • Andrew T. Fenley
    • 1
  • Michael K. Gilson
    • 1
  1. 1.Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of California San DiegoLa JollaUSA

Personalised recommendations