The primary challenge in establishing RBFE calculations using a hybrid topology approach is identifying the largest shared core region in both end-states. The complexity of the phase space can be reduced by merging the atom coordinates of the found core region and therefore enhance the sampling efficiency. Optimal merging of coordinates aims to minimize atomic perturbations and does not reduce the phase space overlap between endstates, therefore lowering the sampling cost of retrieving converged free energy estimations. The following objectives can be outlined for ligand atom mapping: