  Free-energy differences between pairs of end-states can be estimated based on
molecular dynamics (MD) simulations using standard pathway-dependent methods
such as thermodynamic integration (TI), free-energy perturbation, or Bennett's
acceptance ratio. Replica-exchange enveloping distribution sampling (RE-EDS),
on the other hand, allows for the sampling of multiple end-states in a single
simulation without the specification of any pathways. In this work, we use the
RE-EDS method as implemented in GROMOS together with generalized AMBER force
field (GAFF) topologies, converted to a GROMOS-compatible format with a newly
developed GROMOS++ program amber2gromos, to compute relative hydration free
energies for a series of benzene derivatives. The results obtained with RE-EDS
are compared to the experimental data as well as calculated values from the
literature. In addition, the estimated free-energy differences in water and in
vacuum are compared to values from TI calculations carried out with GROMACS.
The hydration free energies obtained using RE-EDS for multiple molecules are
found to be in good agreement with both the experimental data and the results
calculated using other free-energy methods. While all considered free-energy
methods delivered accurate results, the RE-EDS calculations required the least
amount of total simulation time. This work serves as a validation for the use
of GAFF topologies with the GROMOS simulation package and the RE-EDS approach.
Furthermore, the performance of RE-EDS for a large set of 28 end-states is
assessed with promising results.
