Test System Repository
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.
Minimum Content of a Test Set
- Inputs: topology files, starting coordinate file(s), plain text file stating key input parameters (ensemble (NVT, NPT), water model, counterions, T, P, cutoffs). Also, if one used a binding PMF, give the final receptor-ligand distance and how it was defined.
- Output(s): Computed free energy.
Test Sets
The Simple Small Molecule Solvation Benchmark Test Set
- Small Molecule Hydration Benchmark Set 1: 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].
Host-Guest Binding
Perhaps three test cases.
- 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.
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 whether this many ligands are needed for numerical evaluation of methods.
- T4 Lysozyme, polar and apolar sites (methods should be able to get this)
- FKBP (rock solid, well-studied). AMBER parameterized input files in GROMACS format
- Trypsin (well studied, potential issues with sampling and charges it would be good for people to swing at)
- DNA gyrase (from Vertex's data collection curated by Richard Dixon).
- CCP model binding site
References
- ↑ 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
- ↑ 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.