It has been observed that RAMD samples multiple egress pathways and the simulation times of the most frequently sampled (main) path correlate well with experimental residence times. Therefore we postulate that the main egress path is the closest to the lowest free energy path and is likely to capture the essence of the unbinding process. We identify the main egress path using clustering on the set of observed egress paths described with summary waypoints (Figure ). To this end, we need to define a distance (or a metric) that captures the fact that each path starts from the same bound pose but that the ligand may progress differently toward a solvent-exposed conformation, where the ligand is at least 8 Å from any of the protein C ɑ atoms.