In inspecting these trajectories, it was noted that the intermolecular hydrogen bonds and π -π stacking were disrupted early in each run. See Figure for one example of such disruption. Once disrupted, these weak interactions had trouble forming again. Thus, most of the conformers produced were of substantially higher energy than the starting conformer (greater than 12 kcal/mol difference), and were screened out early and excluded from the final ensemble. Not only is this wasteful of compute time, but this preferential exploration of the higher energy space means that increasing the simulation length does not improve the results. In addition, the preferential exploration of this high-energy space during the MTD run means that the low-energy space with hydrogen bonds and π -π stacking intact is poorly explored and thus CREST cannot reliably produce better conformers. Another way to state this problem is that the sampling of slow modes which lead to low-energy conformers is not fast enough in comparison to the sampling of the much more abundant slow modes which disrupt NCIs to guarantee that any low-energy conformers will be found. Under these circumstances, the best conformer found is usually very similar to the starting conformer.