Skip to main content
SpringerLink
Log in

AMOEBA binding free energies for the SAMPL7 TrimerTrip host–guest challenge

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

Abstract

As part of the SAMPL7 host–guest binding challenge, the AMOEBA force field was applied to calculate the absolute binding free energy for 16 charged organic ammonium guests to the TrimerTrip host, a recently reported acyclic cucurbituril-derived clip host structure with triptycene moieties at its termini. Here we report binding free energy calculations for this system using the AMOEBA polarizable atomic multipole force field and double annihilation free energy methodology. Conformational analysis of the host suggests three families of conformations that do not interconvert in solution on a time scale available to nanosecond molecular dynamics (MD) simulations. Two of these host conformers, referred to as the “indent” and “overlap” structures, are capable of binding guest molecules. As a result, the free energies of all 16 guests binding to both conformations were computed separately, and combined to produce values for comparison with experiment. Initial ranked results submitted as part of the SAMPL7 exercise had a mean unsigned error (MUE) from experimental binding data of 2.14 kcal/mol. Subsequently, a rigorous umbrella sampling reference calculation was used to better determine the free energy difference between unligated “indent” and “overlap” host conformations. Revised binding values for the 16 guests pegged to this umbrella sampling reference reduced the MUE to 1.41 kcal/mol, with a correlation coefficient (Pearson R) between calculated and experimental binding values of 0.832 and a rank correlation (Kendall τ) of 0.65. Overall, the AMOEBA results demonstrate no significant systematic error, suggesting the force field provides an accurate energetic description of the TrimerTrip host, and an appropriate balance of solvation and desolvation effects associated with guest binding.

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

Similar content being viewed by others

References

  1. Kim K, Scherman O, Macartney D, Dearden D, Tao Z, Masson E, Keinan E, Nau W, Jonkheijm P, Day A, Kaifer A, Brunsveld L, Isaacs L, Sindelar V (2020). In: Kim K (ed) Cucurbiturils and related macrocycles. Royal Society of Chemistry, London

    Google Scholar 

  2. Barrow SJ, Kasera S, Rowland MJ, del Barrio J, Scherman OA (2015) Cucurbituril-bassed molecular recognition. Chem Rev 115:12320

    CAS  PubMed  Google Scholar 

  3. Ganapati S, Grabitz SD, Murkli S, Scheffenbichler F, Rudolph MI, Zavalij PY, Elkermann M, Isaacs L (2017) Molecular containers bind drugs of abuse in vitro and reverse the hyperlocomotive effect of methamphetamine in rats. ChemBioChem 18:1583

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Abel R, Wang L, Harder ED, Berne BJ, Friesner RA (2017) Advancing drug discovery through enhanced free energy calculations accounts. Chem Res 50:1625

    CAS  Google Scholar 

  5. Williams-Noonan BJ, Yuriev E, Chalmers DK (2018) Free energy methods in drug design: prospects of “alchemical perturbation” in medicinal chemistry. J Med Chem 61:638

    CAS  PubMed  Google Scholar 

  6. Mobley DL, Klimovich PV (2012) Perspective: alchemical free energy calculations for drug discovery. J Chem Phys 137:230901

    PubMed  PubMed Central  Google Scholar 

  7. Cabeza de Vaca I, Qian Y, Vllseck JZ, Tirado-Rives J, Jorgensen WL (2018) Enhanced Monte Carlo methods for modeling proteins including computation of absolute free energies of binding. J Chem Theory Comput 14:3279

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Deng N, Cui D, Zhang BW, Xia J, Cruz J, Levy R (2018) Comparing alchemical and physical pathway methods for computing the absolute binding free energy of charged ligands. Phys Chem Chem Phys 20:17081

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Aldeghi M, Bluck JP, Biggin PC (2018) Absolute alchemical free energy calculations for LIgand binding: a beginner’s guide. Method Mol Biol 1762:199

    CAS  Google Scholar 

  10. Kellett K, Duggan BM, Gilson MK (2019) Facile synthesis of a diverse library of Mono-3-substituted cyclodextrim analogues. Supramol Chem 31:251

    CAS  Google Scholar 

  11. Suating P, Nguyen TN, Ernst NE, Wang Y, Jordan JH, Gibb CLD, Ashbaugh HS, Gibb BC (2020) Proximal charge effects on guest binding to a non-polar pocket. Chem Sci 11:3656

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ndendjio SZ, Liu W, Yvanez N, Meng Z, Zavalij PY, Isaacs L (2020) Triptycene walled glycouril trimer: synthesis and recognition properties. New J Chem 44:338

    CAS  PubMed  Google Scholar 

  13. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Muddana HS, Varnado CD, Bielawski CW, Urbach AR, Isaacs L, Geballe MT, Gilson MK (2012) Blind prediction of host-guest binding affinitiesL a new SAMPL3 challenge. J Comput Aided Mol Des 26:475

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Murkli S, McNeil JN, Isaacs L (2019) Cucurbit[8]uril-guest complexes: blinded dataset for the SAMPL6 challenge. Supramol Chem 31:150

    CAS  Google Scholar 

  16. Yin J, Henriksen NM, Slochower DR, Shirts MR, Chiu MW, Mobley DL (2017) Overview of the SAMPL5 host-guest challenge: are we doing better? J Comput Aided Mol Des 31:1

    CAS  PubMed  Google Scholar 

  17. She N, Moncelet D, Gilberg L, Lu X, Sindelar V, Briken V, Isaacs L (2016) Glycoluril-derived molecular clips are potent and selective receptors for cationic dyes in water. Chem-Eur J 22:15270

    CAS  PubMed  Google Scholar 

  18. Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J Am Chem Soc 117:5179

    CAS  Google Scholar 

  19. 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 31:671

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Robertson MJ, Tirado-Rives J, Jorgensen WL (2015) Improved peptide and protein torsional energetics with the OPLSAA force field. J Chem Theory Comput 11:3499

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ponder JW, Wu C, Ren P, Pande VS, Chodera JD, Mobley DL, Schnieders MJ, Haque I, Lambrecht DS, DiStasio JRA, Head-Gordon M, Clark GNI, Johnson ME, Head-Gordon T (2010) Current status of the AMOEBA polarizable force field. J Phys Chem B 114:2549

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Laury ML, Wang L-P, Pande VS, Head-Gordon T, Ponder JW (2015) Revised parameters for the AMOEBA polarizable atomic multipole water model. J Phys Chem B 119:9423

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ren P, Ponder JW (2003) Polarizable atomic multipole water model for molecular mechanics simulation. J Phys Chem B 107:5933

    CAS  Google Scholar 

  24. Ren P, Wu C, Ponder JW (2011) Polarizable atomic multipole-based molecular mechanics for organic molecules. J Chem Theory Comput 7:3143

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Shi Y, Xia Z, Zhang J, Best R, Wu C, Ponder JW, Ren P (2013) Polarizable atomic multipole-based AMOEBA force field for proteins. J Chem Theory Comput 9:4046

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Xiang JY, Ponder JW (2014) An angular overlap model for Cu(II) ion in the AMOEBA polarizable force field. J Chem Theory Comput 10:298

    CAS  PubMed  Google Scholar 

  27. Zhang C, Lu C, Jing Z, Wu C, Piquemal J-P, Ponder JW, Ren P (2018) AMOEBA polarizable atomic multpole force field for nucleic acids. J Chem Theory Comput 14:2084

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Jiao D, Golubkov PA, Darden TA, Ren P (2008) Calculation of protein-ligand binding free energy by using a polarizable potential. Proc Nat Acad Sci USA 105:6290

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang Q, Edupuganti R, Tavares CDJ, Dalby KN, Ren P (2015) Using docking and alchemical free energy approach to determine the binding mechanism of eEF2K inhibitors and prioritizing the compound synthesis. Front Mol Biosci 2:9

    PubMed  PubMed Central  Google Scholar 

  30. Qi R, Walker B, Jing Z, Yu M, Stancu G, Edupuganti R, Dalby KN, Ren P (2019) Computational and experimental studies of inhibitor design for Aldolase A. J Phys Chem B 123:6034

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rackers JA, Wang Z, Lu C, Laury ML, Lagardere L, Schnieders MJ, Piquemal J-P, Ren P, Ponder JW (2018) Tinker 8: software tools for molecular design. J Chem Theory Comput 14:5273

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Harger M, Li D, Wang Z, Dalby K, Lagardere L, Piquemal J-P, Ponder JW, Ren P (2017) Tinker-openMM: absolute and relative alchemical free energies using AMOEBA on GPUs. J Comput Chem 38:2047

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Smith DGA, Burns LA, Simmonett AC, Parrish RM, Schieber MC, Galvelis R, Kraus P, Kruse H, Di Remigio R, Alenaizan A, James AM, Lehtola S, Misiewicz JP, Scheurer M, Shaw RA, Schriber JB, Xie Y, Glick ZL, Sirianni DA, O’Brien JS, Waldrop JM, Kumar A, Hohenstein EG, Pritchard BP, Brooks BR, Schaefer HF III, Sokolov AY, Patkowski K, DePrince AE III, Bozkaya U, King RA, Evangelista FA, Turney JM, Crawford TD, Sherrill CD (2020) Psi4 1.4: open-source software for high-throughput quantum chemistry. J Chem Phys 152:184108

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Stone AJ (1981) Distributed multipole analysis, or how to describe a molecular charge distribution. Chem Phys Lett 83:233

    CAS  Google Scholar 

  35. Stone AJ, Alderton M (2002) Distributed multipole analysis: methods and applications. Mol Phys 100:221

    Google Scholar 

  36. van Duijnen PT, Swart MJ (1998) Molecular and atomic polarizabilities: Thole’s model revisited. J Phys Chem A 102:2399

    Google Scholar 

  37. Thole BT (1981) Molecular polarizabilities calculated with a modified dipole interaction. Chem Phys 59:341

    CAS  Google Scholar 

  38. Halgren TA (1995a) Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem 17:490

    Google Scholar 

  39. Halgren TA (1995b) Merck molecular force field. II. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions. J Comput Chem 17:520

    Google Scholar 

  40. Halgren TA (1995c) Merck molecular force field. III. Molecular geometries and vibrational frequencies for MMFF94. J Comput Chem 17:553

    Google Scholar 

  41. Halgren TA (1995d) Merck molecular force field. V. Extension of MMFF94 using experimental data additional computational data. J Comput Chem 17:616

    Google Scholar 

  42. Halgren TA, Nachbar RB (1995) Merck molecular force field. IV. Conformational energies and geometries for MMFF94. J Comput Chem 17:587

    Google Scholar 

  43. Tuckerman ME, Berne BJ (1991) Molecular dynamics in systems with multiple time scales: systems with stiff and soft degrees of freedom and with short and long range forces. J Chem Phys 95:8362

    CAS  Google Scholar 

  44. Tuckerman ME, Berne BJ (1992) Reversible multiple time scale molecular dynamics. J Chem Phys 97:1990

    CAS  Google Scholar 

  45. Tuckerman ME, Berne BJ, Rossi A (1990) Molecullar dynamics algorithm for multiple time scales: systems with disparate masses. J Chem Phys 94:1465

    Google Scholar 

  46. Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity-rescaling. J Chem Phys 126:014101

    PubMed  Google Scholar 

  47. Bussi G, Parrinello M (2008) Stochastic thermostats: comparison of local and global schemes. Comput Phys Commun 179:26

    CAS  Google Scholar 

  48. Bussi G, Zykova-Timan T, Parrinello M (2009) Isothermal-isobaric molecular dynamics using stochastic velocity rescaling. J Chem Phys 130:074101

    PubMed  Google Scholar 

  49. Frenkel D, Smit B (2001) Understanding molecular simulation: from algorithms to applications, 2nd edn. Academic Press, New York

    Google Scholar 

  50. Faller R, de Pablo JJ (2002) Constant pressure hybrid molecular dynamics-Monte Carlo simulations. J Chem Phys 116:55

    CAS  Google Scholar 

  51. Zwanzig RW (1954) High-temperature equation of state by a perturbation method. I. Nonpolar gases. J Chem Phys 22:1420

    CAS  Google Scholar 

  52. Bennett CH (1976) Efficient esimation of free energy differences from Monte Carlo data. J Comput Phys 22:245

    Google Scholar 

  53. Hamelberg D, McCammon JA (2004) Standard free energy of releasing a localized water molecule from the binding pockets of proteins: double-decoupling method. J Am Chem Soc 126:7683

    CAS  PubMed  Google Scholar 

  54. Zheng X, Wu C, Ponder JW, Marshall GR (2012) Molecular dynamics of β-hairpin models of epigenetic recognition motifs. J Am Chem Soc 134:15970

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Schnieders MJ, Ponder JW (2007) Polarizable atomic multipole solutes in a generalized Kirkwood Continuum. J Chem Theory Comput 3:2083

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Lu X, Samanta SK, Zavalij PY, Isaacs L (2018) Blurring the lines between host and guest: a chimeric receptor derived from cucurbituril and triptycene. Angew Chem Int Ed 57:8073

    CAS  Google Scholar 

  57. Laury ML, Gordon AS, Ponder JW (2018) Absolute binding free energies for the SAMPL6 Cucurbit[8]uril host-guest challenge via the AMOEBA polarizable force field. J Comput Aided Mol Des 32:1087

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Bogusz S, Cheatham TE III, Brooks BR (1998) Removal of pressure and free energy artifacts in charged periodic systems via net charge corrections to the ewald potential. J Chem Phys 108:7070

    CAS  Google Scholar 

  59. Rocklin GJ, Mobley DL, Dill KA, Hunenberger PH (2013) Calculating the binding free energies of charged species based on explicit-solvent simulations employing lattice-sum methods: an accurate correction scheme for electrostatic finite-size effects. J Chem Phys 139:184103

    PubMed  PubMed Central  Google Scholar 

  60. Roux B, Simonson T (2016) Concepts and protocols for electrostatic free energies. Mol Simul 42:1090

    Google Scholar 

  61. Lin Y-L, Aleksandrov A, Simonson T, Roux B (2014) An overview of electrostatic free energy computations for solutions and proteins. J Chem Theory Comput 10:2690

    CAS  PubMed  Google Scholar 

  62. Chen W, Deng Y, Russell E, Wu Y, Abel R, Wang L (2018) Accurate calculation of relative binding free energies between ligands with different net charges. J Chem Theory Comput 14:6346

    CAS  PubMed  Google Scholar 

  63. Liu C, Piquemal J-P, Ren P (2020) Implementation of geometry-dependent charge flux into the polarizable AMOEBA+ potential. J Phys Chem Lett 11:419

    CAS  PubMed  Google Scholar 

  64. Rackers JA, Ponder JW (2019) Classical pauli repulsion: an ansiotropic multipole model. J Chem Phys 150:084104

    PubMed  PubMed Central  Google Scholar 

  65. Bell DR, Qi R, Jing Z, Xiang JY, Meijas C, Schnieders MJ, Ponder JW, Ren P (2016) Calculating binding free energies of host-guest systems using the AMOEBA polarizable force field. Phys Chem Chem Phys 18:30261

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Jiang W, Roux B (2010) Free energy perturbation hamiltonian replica-exchange molecular dynamics (FEP/H-REMD) for absolute ligand binding free energy calculations. J Chem Theory Comput 6:2559

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Liu P, Kim B, Friesner RA, Berne BJ (2005) Replica exchange with solute tempering: a method for sampling biological systems in explicit water. Proc Nat Acad Sci USA 102:13749

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Zheng L, Chen M, Yang W (2008) Random walk in orthogonal space to achieve efficient free-energy simulation of complex systems. Proc Nat Acad Sci USA 105:20227

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the organizers and experimentalists involved with the SAMPL7 challenge for providing an interesting and challenging exercise. We gratefully acknowledge Dr. Chris Ho for help with automating AMOEBA parameter generation for the guest molecules. JWP wishes to thank the National Institutes of Health NIGMS for financial support via awards R01 GM106137 and R01 GM114237.

Author information

Authors and Affiliations

  1. Department of Chemistry, Washington University in St. Louis, Saint Louis, MO, 63130, USA

    Yuanjun Shi, Marie L. Laury, Zhi Wang & Jay W. Ponder

  2. Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO, 63110, USA

    Jay W. Ponder

Authors
  1. Yuanjun Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marie L. Laury
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jay W. Ponder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jay W. Ponder.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, Y., Laury, M.L., Wang, Z. et al. AMOEBA binding free energies for the SAMPL7 TrimerTrip host–guest challenge. J Comput Aided Mol Des 35, 79–93 (2021). https://doi.org/10.1007/s10822-020-00358-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-020-00358-2

Keywords

Search

Navigation