Test System Repository

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Purpose of Test Sets

One of the biggest challenges to carefully validating and comparing free energy methods is defining and sharing well-defined test cases (molecular systems and force field parameters) with reliably known numerical results. If one is not sure of the value of the free energy dictated by the energy model and other physical parameters, it is impossible to make fine comparisons among methods. Additionally, different programs with different bookkeeping, or parameters that have been rounded in some way, can cause legitimate small differences between computed free energies, obscuring differences in the methods. The goal of this Repository is to help define and disseminate a stable set of test systems of varied nature and complexity for use by the free energy simulation community. Note that the free energies provided by these systems may not agree particularly well with experiment, but this is not necessary, because the purpose here is to test the numerical performance of the methods.

To join a mailing list for a discussion of protein-ligand binding benchmarks, email michael.shirts at virginia.edu. If you have signed up previously, you can log into the discussion (password protected) at https://collab.itc.virginia.edu/portal/xlogin

Specifications of the content of binding benchmark tests

Current standards version is 0.5, dated Sept 27, 2013

There will be three types of depositions for the binding benchmark test sets:

All tests consist of a system specification and at least one potential energy result from a specified software version. After that, multiple people can contribute free energy results for the same system specification and potential energy result, or contribute potential energy results of the system for different simulation codes. They also might propose a new potential energy result based on their own preferences for simulations of the system (different cutoffs, etc). Importantly, the "free energy results" should be an attempt to be independent of any such nonphysical approximations.

Test Sets

Small Molecule Solvation Benchmark Sets

  • The Simple Small Molecule Solvation Benchmark Test Set: This test set was designed to test methods for computing hydration free energies of small molecules. It comprises a series of small molecules, parameter sets for three different software codes, and reference energies [1].
  • FreeSolv (Mobley) Hydration Set: This is an extensive (640+) molecule database of experimental and calculated hydration free energies for small neutral molecules. It includes GROMACS topology and coordinate files as well.

Host-Guest Binding

  • Cucurbit[7]uril with benzene (partial charges artificially set to zero). This tests binding of a nonpolar guest that encounters little barrier to exiting a rigid host.
  • Cucurbit[7]uril with guest B5 [2]. This tests binding of a bulky cationic guest that encounters a substantial energy barrier to exiting a rigid host.
  • Some guest binding beta-cyclodextrin. This would test binding to a much more flexible host.
  • Octa-acid with benzoic acid guest derivatives (from SAMPL4 and SAMPL5 blind prediction challenge)[3].

Protein-Ligand Binding

The following test systems were proposed at the 2012 Workshop on Free Energy Methods in Drug Design. One proposal would be to include 5-10 ligands. However, we should discuss how many ligands are needed for numerical evaluation of methods.


  1. Paliwal, H and Shirts, M. R. (2011) An efficient method for the calculation of quantum mechanics/molecular mechanics free energies. J. Chem. Theory Comp. 7(12): 4115-4134, J. Chem. Theory Comput. - Find at Cite-U-Like
  2. Moghaddam,S., Yang,C., Rekharsky,M., Ko,Y.H., Kim,K., Inoue,Y., and Gilson,M.K. (2011) New Ultrahigh Affinity Host - Guest Complexes of Cucurbit[7]uril with Bicyclo[2.2.2]octane and Adamantane Guests: Thermodynamic Analysis and Evaluation of M2 Affinity Calculations. J.Am.Chem.Soc. 133:3570-3581.
  3. Olsson, M. A., Söderhjelm, P., Ryde U. (2016). J. Comp. Chem. 37:1589-1600.
  4. Boyce, S. E., Mobley, D. L., Rocklin, G. J., Graves, A. P., Dill, K. A. and Shoichet, B. K. (2009) Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site. J. Mol. Biol. 394:747-763.
  5. Rocklin, G. J., Boyce, S. E., Fischer, M., Fish, I, Mobley, D. L., Shoichet, B. K., Dill, K. A. (2013) Blind prediction of charged ligand binding affinities in a model binding site. J. Mol. Biol. 425:4569-4583.
  6. Aldeghi, M., Heifetz, A., Bodkin, M. J., Knapp, S., Biggin, P.C (2016). Accurate calculation of the absolute free energy of binding for drug molecules. Chem Sci. 7:207-218.