RE-EDS Using GAFF Topologies: Application to Relative Hydration Free-Energy Calculations for Large Sets of Molecules

TL;DR

This study demonstrates that RE-EDS combined with GAFF topologies in GROMOS efficiently computes relative hydration free energies for multiple molecules, matching experimental and literature data with less simulation time.

Contribution

The paper introduces a novel workflow using RE-EDS with GAFF topologies in GROMOS, validated for large sets of molecules, improving efficiency in free-energy calculations.

Findings

RE-EDS yields hydration free energies in good agreement with experimental data.

RE-EDS requires less simulation time than traditional methods.

The approach is validated for 28 molecules, showing promising scalability.

Abstract

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.