Across the RAMD trajectories, the ligand initially stays unperturbed in the binding site as the RAMD samples vector direction to bias the unbinding of the ligand (Figure ). This portion of the trajectory provides minimal variation with respect to the input pose and does not contribute to our understanding of how the ligand unbinds. Consequently, we consider this portion of the trajectory "unproductive" and exclude these frames to generate a "reactive" trajectory focusing on the ligand's unbinding process (Figure ). To generate the reactive trajectory from RAMD simulation we extract the frames in the time interval between the first frame where the ligand is solvent exposed (MinDist >8 Å and at least 5 Å of ligand RMSD from the initial pose) and backward towards the beginning of the detachment process (MinDist >6 Å or at least 2 Å of ligand RMSD from the initial pose). We supplement this set with the initial bound frame (Figure ). Figure . A) Initial trajectory frames from RAMD. B) Trajectory is processed backward to identify the sections that are solvent exposed, the ones that are part of the reactive trajectory, and the pre-reactive sections where RAMD was unproductive. C) The resulting set of frames is then saved as an initial set of waypoints to be further processed to create the summary trajectory, including the first frame which is assumed to be the bound pose and the first solvent-exposed trajectory frame. D) This set is then refined with a Monte Carlo procedure to select a given number of waypoints that, together with the initial frame (pre-reactive in red) and the first solvent exposed frame (cyan), will form the initial rough path. E) This set of waypoints is interpolated to achieve a predetermined resolution (smooth path-purple).