The Simple Molecular Benchmark Test Set

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Simple Molecule Benchmark Test Set (v1.0)

Ideally test systems should have zero free energy, though this is not generally possible With a zero transformation, then it is necessary to partially specify the path, so that particularly clever methods do not manage to solve the problem in ways that would not be valid in general simulations. Because of this, the zero transformations here are defined with the endpoints and one midpoint along the transformation. This ensures that a large transformation is performed, but allows these systems to be used to improve free energy pathways as well.

Problem 1) Is the method at all valid for molecular systems?

• System: Simplest molecular free energy system = UA methane in TIP3P water.

• Notes: There are no bond, angle or torsions terms, or solute/solvent charge: this is the simplest system that can be truly defined as realistic.

Problem 2) Can the method handle water rearrangement around charges?

• System: Charged dipole on two LJ spheres tethered together. The Lennard-Jones and bond length terms are taken from UA ethane, with +/- 1 charges.

• Notes: This setup allows avoidance of computing free energies of ions directly, which is still not handled completely correctly in many codes.

Problem 3) Can the free energy method handle multiple atomic sites efficiently?

• System: Anthracene solvation in water in TIP3P water

• Notes: No ligand degrees of freedom to complicate the analysis. Null transforms are possible, but these have ended up particularly difficult to implement in different simulation packages. We are deciding whether this could also perform the anthracene->benzene->anthracene transformation.

Available Files

In each case, we have including 100 starting configurations for each system, specifying initial box size and positions, and all other input files. We also list the exact energies of the starting configurations to make it easy to verify input files for additional programs.

• README File:
  • README

• Comparisons of energies evaluated:
  • Energy Comparisons

• GROMACS Files:
  • GROMACS

• AMBER Files:
  • AMBER

• DESMOND Files
  • DESMOND

Improvements to the Benchmark Test Set

Extensions to other programs

We are interested in getting validated comparisons with the following systems

• GROMOS

• CHARMM

• NAMD

• DL_POLY

• TINKER

• LAMMPS

Future simple molecular sets problems to tackle

Additional Problem 1) Can the method handle long time scale barriers along torsional degrees of freedom?

• Potential system: 1-octanol -> ethane -> 1-octanol in TIP3P water.

• Notes: Topologically, the system would be set up as HO-(CH2)14-OH, with the middle two carbons remaining coupled to the environment for the entire transformation. The h-bonds between alcohols and water might hopefully slow down the torsional sampling.

Additional Problem 2) Can the method handle complex small molecules?

• Future System: Complicated substituted aromatic like Imatinib, with three substituted positions, with the transformation to cycle the substituents to different positions along the aromatic with benzene as the intermediate.

Estimators of the uncertainty should be validated against uncertainty generated directly from runs from independent configurations (100), and should include the computation of the correlation time of the observable used to calculate the uncorrelated samples used in the free energies (such as the potential energy differences or dH/dL).