Relative binding free Energy calculations in GROMACS between dissimilar molecules using bidirectional nonequilibrium dual topology schemes

We describe a step-by-step protocol for the computation of relative dissociation free energies with GROMACS, based on a novel bidirectional nonequilibrium alchemical approach. The proposed methodology does not require any intervention in the code. It allows computing with good accuracy the RBFE between small molecules with arbitrary differences in volume, charge, and chemical topology. The procedure is illustrated for the challenging SAMPL9 batch on the tutorial https://procacci.github.io/vdssb_gromacs/NE-RDFE