Where |X(t)-F i | is the RMSD between the current ligand heavy atom positions (X(t)) and the atomic positions of the i-th waypoint of the egress path F i . The ligand RMSD is calculated after optimal alignment to the binding pocket, defined as the set of backbone atoms within 8 Å to the ligand in its bound pose. The parameter λ is calculated as 2.3/DeltaMax 2 where DeltaMax is the maximum RMSD between the same ligand in two adjacent waypoints in the path CVs. The progress along the path variable (S, Eq. 2) describes the fluctuations along the egress path by measuring the nearest waypoint indices while the distance from the path (Z, Eq. 3) describes the mean square distance from the egress path allowing accurate sampling of the binding pocket. Determination of the S and Z CVs for each protein-ligand complex captures the specifics of each unbinding process and automates the choice of CVs. Note that in this specific formalism, only the fluctuations of ligand atoms' positions relative to receptor atoms are explicitly enhanced. An extension of this approach could be devised to explicitly consider the involved receptor residues which we leave for future work.