In general, it is non-trivial to select the optimum receptor-ligand restraints. Furthermore, ABFE calculations can be challenging to converge and therefore computationally costly because the ligand is completely removed. As a result, application studies still the application of large forces, which can cause simulations to crash. This frequently occurs when sets of three contiguous anchor points approach collinearity, which can result in the application of large forces through the dihedral restraints.