Journal of Computer-Aided Molecular Design

, Volume 31, Issue 1, pp 107–118 | Cite as

Absolute binding free energies for octa-acids and guests in SAMPL5

Evaluating binding free energies for octa-acid and guest complexes in the SAMPL5 blind challenge
  • Florentina TofoleanuEmail author
  • Juyong Lee
  • Frank C. Pickard IV
  • Gerhard König
  • Jing Huang
  • Minkyung Baek
  • Chaok Seok
  • Bernard R. Brooks


As part of the SAMPL5 blind prediction challenge, we calculate the absolute binding free energies of six guest molecules to an octa-acid (OAH) and to a methylated octa-acid (OAMe). We use the double decoupling method via thermodynamic integration (TI) or Hamiltonian replica exchange in connection with the Bennett acceptance ratio (HREM-BAR). We produce the binding poses either through manual docking or by using GalaxyDock-HG, a docking software developed specifically for this study. The root mean square deviations for our most accurate predictions are 1.4 kcal mol−1 for OAH with TI and 1.9 kcal mol−1 for OAMe with HREM-BAR. Our best results for OAMe were obtained for systems with ionic concentrations corresponding to the ionic strength of the experimental solution. The most problematic system contains a halogenated guest. Our attempt to model the σ-hole of the bromine using a constrained off-site point charge, does not improve results. We use results from molecular dynamics simulations to argue that the distinct binding affinities of this guest to OAH and OAMe are due to a difference in the flexibility of the host. We believe that the results of this extensive analysis of host-guest complexes will help improve the protocol used in predicting binding affinities for larger systems, such as protein-substrate compounds.


Binding free energy simulations Thermodynamic integration Hamiltonian replica exchange Bennett acceptance ratio Double decoupling method Molecular dynamics simulations GalaxyDock-HG 



The authors would like to thank Tim Miller, Richard Venable and John Legato for technical assistance. We would also like to thank Richard Pastor for very helpful discussions concerning the importance of accurately evaluating the ionic concentration. We extend our gratitude to Andrew C. Simmonett and Michael Lerner for helpful comments on the manuscript. This work was partially supported by the intramural research program of the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health and employed the high-performance computational capabilities of the LoBoS and Biowulf Linux clusters at the National Institutes of Health. ( and ( Florentina Tofoleanu, Juyong Lee and Frank Pickard have been supported by the NHLBI Intramural Lenfant Biomedical Fellowship.

Supplementary material

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Supplementary material 1 (pdf 1236 KB)


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Copyright information

© Springer International Publishing Switzerland (outside the USA) 2016

Authors and Affiliations

  1. 1.Laboratory of Computational BiologyNational Institutes of Health – National Heart, Lung, and Blood InstituteRockvilleUSA
  2. 2.Max-Planck-Institut für KohlenforschungMülheim an der RuhrGermany
  3. 3.Department of Pharmaceutical Science, School of PharmacyUniversity of MarylandBaltimoreUSA
  4. 4.Department of ChemistrySeoul National UniversitySeoulRepublic of Korea

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