Using AMBER18 for Relative Free Energy Calculations

With renewed interest
in free energy methods in contemporary structure-based
drug design, there is a pressing need to validate against multiple
targets and force fields to assess the overall ability of these methods
to accurately predict relative binding free energies. We computed
relative binding free energies using graphics processing unit accelerated
thermodynamic integration (GPU-TI) on a data set originally assembled
by Schrödinger, Inc. Using their GPU free energy code (FEP+)
and the OPLS2.1 force field combined with the REST2 enhanced sampling
approach, these authors obtained an overall MUE of 0.9 kcal/mol and
an overall RMSD of 1.14 kcal/mol. In our study using GPU-TI from AMBER
with the AMBER14SB/GAFF1.8 force field but without enhanced sampling,
we obtained an overall MUE of 1.17 kcal/mol and an overall RMSD of
1.50 kcal/mol for the 330 perturbations contained in this data set.
A more detailed analysis of our results suggested that the observed
differences between the two studies arise from differences in sampling
protocols along with differences in the force fields employed. Future
work should address the problem of establishing benchmark quality
results with robust statistical error bars obtained through multiple
independent runs and enhanced sampling, which is possible with the
GPU-accelerated features in AMBER.