Molecular dynamics (MD) simulations have proven their usefulness in studying many kinds of biological processes, including intracellular dynamics, 1 protein folding, and capturing ligand-binding pathways. Among the goals that MD can target is the accurate calculation of association/dissociation free energies of, for example, protein-protein, protein-ligand, protein-DNA, and ligand-membrane systems. For that, one would want to use MD to estimate absolute binding free energies (ABFE). While relative binding free energy (RBFE) calculations have already matured and are now almost routinely used in industrial workflows, ABFE calculations are in general more complicated, require more resources, and are still under development. The performance of methods for calculating ABFE is regularly assessed in the SAMPL challenge, and currently, a typical error in ABFE calculations is twice as high as in RBFE (mean absolute error of ∼2 kcal/mol for the best ABFE method versus <1 kcal/mol for RBFE methods ).