Skip to main content
Log in

SAMPL5: 3D-RISM partition coefficient calculations with partial molar volume corrections and solute conformational sampling

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

Abstract

Implicit solvent methods for classical molecular modeling are frequently used to provide fast, physics-based hydration free energies of macromolecules. Less commonly considered is the transferability of these methods to other solvents. The Statistical Assessment of Modeling of Proteins and Ligands 5 (SAMPL5) distribution coefficient dataset and the accompanying explicit solvent partition coefficient reference calculations provide a direct test of solvent model transferability. Here we use the 3D reference interaction site model (3D-RISM) statistical-mechanical solvation theory, with a well tested water model and a new united atom cyclohexane model, to calculate partition coefficients for the SAMPL5 dataset. The cyclohexane model performed well in training and testing (\(R=0.98\) for amino acid neutral side chain analogues) but only if a parameterized solvation free energy correction was used. In contrast, the same protocol, using single solute conformations, performed poorly on the SAMPL5 dataset, obtaining \(R=0.73\) compared to the reference partition coefficients, likely due to the much larger solute sizes. Including solute conformational sampling through molecular dynamics coupled with 3D-RISM (MD/3D-RISM) improved agreement with the reference calculation to \(R=0.93\). Since our initial calculations only considered partition coefficients and not distribution coefficients, solute sampling provided little benefit comparing against experiment, where ionized and tautomer states are more important. Applying a simple \(\hbox {p}K_{\text {a}}\) correction improved agreement with experiment from \(R=0.54\) to \(R=0.66\), despite a small number of outliers. Better agreement is possible by accounting for tautomers and improving the ionization correction.

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

Access this article

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

Similar content being viewed by others

References

  1. Palmer DS, Frolov AI, Ratkova EL, Fedorov MV (2010) J Phys Condens Matter 22(49):492101. doi:10.1088/0953-8984/22/49/492101. http://stacks.iop.org/0953-8984/22/i=49/a=492101

  2. Truchon JF, Pettitt BM, Labute P (2014) J Chem Theory Comput 10(3):934. doi:10.1021/ct4009359

    Article  CAS  Google Scholar 

  3. Sergiievskyi V, Jeanmairet G, Levesque M, Borgis D (2015) J Chem Phys 143(18):184116. doi:10.1063/1.4935065. http://scitation.aip.org/content/aip/journal/jcp/143/18/10.1063/1.4935065

  4. Misin M, Fedorov MV, Palmer DS (2015) J Chem Phys 142(9):091105. doi:10.1063/1.4914315. http://scitation.aip.org/content/aip/journal/jcp/142/9/10.1063/1.4914315

  5. Misin M, Fedorov MV, Palmer DS (2016) J Phys Chem B 120(5):975. doi:10.1021/acs.jpcb.5b10809

    Article  Google Scholar 

  6. Ratkova EL, Palmer DS, Fedorov MV (2015) Chem Rev 115(13):6312. doi:10.1021/cr5000283

    Article  CAS  Google Scholar 

  7. Kovalenko A, Hirata F (2000) J Chem Phys 113(7):2793. doi:10.1063/1.1305885. http://scitation.aip.org/content/aip/journal/jcp/113/7/10.1063/1.1305885

  8. Kido K, Yokogawa D, Sato H (2012) J Chem Phys 137(2):024106. doi:10.1063/1.4733393. http://scitation.aip.org/content/aip/journal/jcp/137/2/10.1063/1.4733393

  9. Joung IS, Luchko T, Case DA (2013) J Chem Phys 138(4):044103. doi:10.1063/1.4775743. http://jcp.aip.org/resource/1/jcpsa6/v138/i4/p044103_s1

  10. Kovalenko A, Hirata F (2000) J Chem Phys 112(23):10391. doi:10.1063/1.481676. http://scitation.aip.org/content/aip/journal/jcp/112/23/10.1063/1.481676

  11. Kovalenko A, Hirata F (2000) J Chem Phys 112(23):10403. doi:10.1063/1.481677. http://scitation.aip.org/content/aip/journal/jcp/112/23/10.1063/1.481677

  12. Johnson J, Case DA, Yamazaki T, Gusarov S, Kovalenko A, Luchko T (2016) J Phys Condens Matter 28(34):344002. doi:10.1088/0953-8984/28/34/344002. http://stacks.iop.org/0953-8984/28/i=34/a=344002

  13. Ten-no S, Jung J, Chuman H, Kawashima Y (2010) Mol Phys 108(3–4):327. doi:10.1080/00268970903451848

    Article  CAS  Google Scholar 

  14. Huang W, Blinov N, Kovalenko A (2015) J Phys Chem B 119(17):5588. doi:10.1021/acs.jpcb.5b01291

    Article  CAS  Google Scholar 

  15. Misin M, Palmer DS, Fedorov MV (2016) J Phys Chem B 120(25):5724. doi:10.1021/acs.jpcb.6b05352

    Article  CAS  Google Scholar 

  16. Bannan CC, Burley KH, Chiu M, Shirts MR, Gilson MK, Mobley DL (2016) J Comput Aided Mol Des. doi:10.1007/s10822-016-9954-8

  17. Rustenburg AS, Justin Dancer BL, Ortwine DF, Mobley DL, Chodera JD (2016) J Comput Aided Mol Des (in press)

  18. Tielker N, Tomazic D, Heil J, Ehrhart TKS, GÃŒssregen S, Schmidt KF, Kast SM (2016) J Comput Aided Mol Des (in press)

  19. Luchko T, Gusarov S, Roe DR, Simmerling C, Case DA, Tuszynski J, Kovalenko A (2010) J Chem Theory Comput 6(3):607. doi:10.1021/ct900460m

    Article  CAS  Google Scholar 

  20. Omelyan I, Kovalenko A (2015) J Chem Theory Comput 11(4):1875. doi:10.1021/ct5010438

    Article  CAS  Google Scholar 

  21. Miyata T, Hirata F (2007) J Comput Chem 29:871

    Article  Google Scholar 

  22. Omelyan I, Kovalenko A (2013) J Chem Phys 139(24):244106. doi:10.1063/1.4848716. http://scitation.aip.org/content/aip/journal/jcp/139/24/10.1063/1.4848716

  23. Kovalenko A (2003) In: Hirata F (ed) Molecular theory of solvation, understanding chemical reactivity, vol 24. Kluwer Academic Publishers, Dordrecht, pp 169–275

    Chapter  Google Scholar 

  24. Beglov D, Roux B (1997) J Phys Chem B 101(39):7821

    Article  CAS  Google Scholar 

  25. Kovalenko A, Hirata F (1999) J Chem Phys 110(20):10095

    Article  CAS  Google Scholar 

  26. Hansen JP, McDonald IR (1986) Theory of simple liquids. Academic Press, London

    Google Scholar 

  27. Hirata F (2003) In: Hirata F (ed) Molecular theory of solvation, understanding chemical reactivity, vol 24. Kluwer Academic Publishers, Dordrecht, pp 1–60

    Chapter  Google Scholar 

  28. Perkyns JS, Pettitt BM (1992) Chem Phys Lett 190(6):626

    Article  CAS  Google Scholar 

  29. Hirata F, Pettitt BM, Rossky PJ (1982) J Chem Phys 77(1):509. doi:10.1063/1.443606. http://scitation.aip.org/content/aip/journal/jcp/77/1/10.1063/1.443606

  30. Hirata F, Rossky PJ, Pettitt BM (1983) J Chem Phys 78(6):4133. doi:10.1063/1.445090. http://scitation.aip.org/content/aip/journal/jcp/78/6/10.1063/1.445090

  31. Kovalenko A (2013) Pure Appl Chem 85(1):159. doi:10.1351/PAC-CON-12-06-03

    Article  CAS  Google Scholar 

  32. Yamazaki T, Blinov N, Wishart D, Kovalenko A (2008) Biophys J 95(10):4540. doi:10.1529/biophysj.107.123000. http://www.sciencedirect.com/science/article/pii/S0006349508785953

  33. Imai T, Ohyama S, Kovalenko A, Hirata F (2007) Protein Sci 16(9):1927

    Article  CAS  Google Scholar 

  34. Drabik P, Gusarov S, Kovalenko A (2007) Biophys J 92(2):394

    Article  CAS  Google Scholar 

  35. Harano Y, Imai T, Kovalenko A, Kinoshita M, Hirata F (2001) J Chem Phys 114(21):9506

    Article  CAS  Google Scholar 

  36. Imai T, Harano Y, Kinoshita M, Kovalenko A, Hirata F (2007) J Chem Phys 126(22):225102

    Article  Google Scholar 

  37. Imai T, Harano Y, Kinoshita M, Kovalenko A, Hirata F (2006) J Chem Phys 125(2):024911

    Article  Google Scholar 

  38. Imai T, Hiraoka R, Kovalenko A, Hirata F (2007) Proteins Struct Funct Bioinform 66(4):804

    Article  CAS  Google Scholar 

  39. Imai T, Hiraoka R, Seto T, Kovalenko A, Hirata F (2007) J Phys Chem B 111(39):11585

    Article  CAS  Google Scholar 

  40. Imai T, Isogai H, Seto T, Kovalenko A, Hirata F (2006) J Phys Chem B 110(24):12149

    Article  CAS  Google Scholar 

  41. Imai T, Kovalenko A, Hirata F (2006) Mol Simul 32(10–11):817

    Article  CAS  Google Scholar 

  42. Imai T, Hiraoka R, Kovalenko A, Hirata F (2005) J Am Chem Soc 127(44):15334

    Article  CAS  Google Scholar 

  43. Huang W, Blinov N, Kovalenko A (2015) J Phys Chem B 119(17):5588. doi:10.1021/acs.jpcb.5b01291

    Article  CAS  Google Scholar 

  44. Stumpe MC, Blinov N, Wishart D, Kovalenko A, Pande VS (2011) J Phys Chem B 115(2):319. doi:10.1021/jp102587q

    Article  CAS  Google Scholar 

  45. Kaminski JW, Gusarov S, Wesolowski TA, Kovalenko A (2010) J Phys Chem A 114(20):6082. doi:10.1021/jp100158h

    Article  CAS  Google Scholar 

  46. Kast SM, Kloss T (2008) J Chem Phys 129(23):236101. doi:10.1063/1.3041709. http://scitation.aip.org/content/aip/journal/jcp/129/23/10.1063/1.3041709

  47. Imai T, Kinoshita M, Hirata F (2000) J Chem Phys 112(21):9469. doi:10.1063/1.481565. http://scitation.aip.org/content/aip/journal/jcp/112/21/10.1063/1.481565

  48. Tuckerman ME, Berne BJ, Martyna GJ (1991) J Chem Phys 94(10):6811. doi:10.1063/1.460259. http://scitation.aip.org/content/aip/journal/jcp/94/10/10.1063/1.460259

  49. Tuckerman M, Berne BJ, Martyna GJ (1992) J Chem Phys 97(3):1990. doi:10.1063/1.463137. http://scitation.aip.org/content/aip/journal/jcp/97/3/10.1063/1.463137

  50. Ng K (1974) J Chem Phys 61(7):2680. doi:10.1063/1.1682399. http://scitation.aip.org/content/aip/journal/jcp/61/7/10.1063/1.1682399

  51. Mobley DL, Dill KA, Chodera JD (2008) J Phys Chem B 112(3):938. doi:10.1021/jp0764384

    Article  CAS  Google Scholar 

  52. Gilson MK, Given JA, Bush BL, McCammon JA (1997) Biophys J 72(3):1047. doi:10.1016/S0006-3495(97)78756-3. http://www.cell.com/article/S0006349597787563/abstract

  53. Zwanzig RW (1954) J Chem Phys 22(8):1420. doi:10.1063/1.1740409. http://scitation.aip.org/content/aip/journal/jcp/22/8/10.1063/1.1740409

  54. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comput Chem 25(9):1157. doi:10.1002/jcc.20035. http://onlinelibrary.wiley.com/doi/10.1002/jcc.20035/abstract

  55. Case DA, Babin V, Berryman JT, Betz RM, Cai Q, Cerutti DS, Cheatham TE, Darden TA, Duke RE, Gohlke H, Goetz AW, Gusarov S, Homeyer N, Janowski P, Kaus J, Kolossváry I, Kovalenko A, Lee TS, Le Grand S, Luchko T, Luo R, Madej B, Merz K, Paesani F, Roe DR, Roitberg AE, Sagui C, Salomon-Ferrer R, Seabra G, Simmerling C, Smith W, Swails JM, Walker RC, Wang J, Wolf RM, Wu X, Kollman PA (2015) AMBER 2015. University of California, San Francisco

  56. Li J, Zhu T, Hawkins GD, Winget P, Liotard DA, Cramer CJ, Truhlar DG (1999) Theor Chem Acc 103(1):9. doi:10.1007/s002140050513. http://link.springer.com/article/10.1007/s002140050513

  57. Radzicka A, Wolfenden R (1988) Biochemistry 27(5):1664. doi:10.1021/bi00405a042

    Article  CAS  Google Scholar 

  58. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH (2016) Nucleic Acids Res 44(D1):D1202. doi:10.1093/nar/gkv951. http://nar.oxfordjournals.org/content/44/D1/D1202

  59. O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR (2011) J Cheminform 3(1):33. doi:10.1186/1758-2946-3-33. http://www.jcheminf.com/content/3/1/33/abstract

  60. National Center for Biotechnology Information. PubChem Compound Database; CID=8078. https://pubchem.ncbi.nlm.nih.gov/compound/8078. Accessed 14 Jan 2016

  61. Perkyns J, Pettitt BM (1992) J Chem Phys 97(10):7656. doi:10.1063/1.463485. http://scitation.aip.org/content/aip/journal/jcp/97/10/10.1063/1.463485

  62. Hirata F, Rossky PJ (1981) Chem Phys Lett 83(2):329. doi:10.1016/0009-2614(81)85474-7. http://www.sciencedirect.com/science/article/pii/0009261481854747

  63. Yang L, Tan Ch, Hsieh MJ, Wang J, Duan Y, Cieplak P, Caldwell J, Kollman PA, Luo R (2006) J Phys Chem B 110(26):13166. doi:10.1021/jp060163v. http://pubs.acs.org/doi/abs/10.1021/jp060163v

  64. Schuler LD, Daura X, van Gunsteren WF (2001) J Comput Chem 22(11):1205. doi:10.1002/jcc.1078. http://onlinelibrary.wiley.com/doi/10.1002/jcc.1078/abstract

  65. Chandler D, Andersen HC (1972) J Chem Phys 57(5):1930. doi:10.1063/1.1678513. http://scitation.aip.org/content/aip/journal/jcp/57/5/10.1063/1.1678513

  66. Aicart E, Tardajos G, Diaz Pena M (1980) J Chem Eng Data 25(2), 140. doi:10.1021/je60085a007. http://dx.doi.org/10.1021/je60085a007

  67. Anikeenko AV, Kim AV, Medvedev NN (2010) J Struct Chem 51(6), 1090. http://link.springer.com/article/10.1007/s10947-010-0167-z

  68. Shumway RH, Stoffer DS (2010) Time series analysis and its applications: with R examples. Springer, Berlin

    Google Scholar 

  69. chemicalize.org was used for prediction of acid and base pk\(_a\) values (2016) http://www.chemaxon.com. Chemicalize.org and ChemAxon

  70. Manchester J, Walkup G, Rivin O, You Z (2010) J Chem Inf Model 50(4):565. doi:10.1021/ci100019p

    Article  CAS  Google Scholar 

  71. MacCallum JL, Tieleman DP (2003) J Comput Chem 24(15):1930. doi:10.1002/jcc.10328. http://onlinelibrary.wiley.com/doi/10.1002/jcc.10328/abstract

  72. Villa A, Mark AE (2002) J Comput Chem 23(5):548. doi:10.1002/jcc.10052. http://onlinelibrary.wiley.com/doi/10.1002/jcc.10052/abstract

  73. Chang J, Lenhoff AM, Sandler SI (2007) J Phys Chem B 111(8):2098. doi:10.1021/jp0620163

    Article  CAS  Google Scholar 

  74. Oostenbrink C, Villa A, Mark AE, Van Gunsteren WF (2004) J Comput Chem 25(13):1656. doi:10.1002/jcc.20090. http://onlinelibrary.wiley.com/doi/10.1002/jcc.20090/abstract

Download references

Acknowledgments

The authors would like to thank Caitlin C. Bannan and David L. Mobley for access to the results from their explicit solvent reference calculations. T.L. would like to additionally thank David Mobley and Stefan Kast for useful discussions about calculating solvation free energies from time series. This work was partially supported by the California State University Program for Education and Research in Biotechnology (CSUPERB; T.L., G.C.L., K.P.J.) and by the Alberta Prion Research Institute and the National Research Council of Canada (N.B., A.K.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tyler Luchko.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10822_2016_9947_MOESM1_ESM.pdf

The online version of this article contains supplementary material, including discussion of conformational sampling issues, partition coefficients for neutral amino acid side chains, solvation free energies computed by alternate thermodynamic paths, and \(\hbox {p}K_{\text {a}}\) predictions.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luchko, T., Blinov, N., Limon, G.C. et al. SAMPL5: 3D-RISM partition coefficient calculations with partial molar volume corrections and solute conformational sampling. J Comput Aided Mol Des 30, 1115–1127 (2016). https://doi.org/10.1007/s10822-016-9947-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-016-9947-7

Keywords

Navigation