for the core region (see Figure ). Figure : When considering an end-state A (depicted in dark blue) and an end-state B (depicted in beige), there exist three distinct approaches for representing the systems in free energy calculations: Single Topology, employing a minimal set of coordinates for both end-states (green merged atoms); Hybrid Topology, which merges shared parts into a core region and uses dual-topology-like regions for differing regions; and Dual Topology, where the coordinates of both end-states are kept separate. In the realm of dual topology, various approaches are found in literature, including the unconstrained case, the separated dual topology approach using orientational restraints, and the linked dual topology approach, connecting the end-states with restraints.