Taken together, these factors usually result in substantially better exploration of the lowenergy potential energy surface than the iMTD algorithm gives, but here the performance is illustrated as slightly inferior, to be conservative. Panel d shows the second cycle of the modified algorithm. In this cycle, MTD runs are started from three conformers, in the G, H, and K potential wells. Conformers from I are not used as starting points, as they are too similar to the already used conformer from the first cycle, and those from J are not used, as the ratio of their energy (relative to the best conformer found so far, in well H) to RMSD (from the starting point of cycle 1) is too large. Usually, the algorithm will run 12 conformers per cycle, but in this illustration, at least within this slice of the PES, only up to three can be chosen within the constraints. In this panel, conformer dots are colourcoded to match the arrow indicating the starting position of the MTD run that produced them. Panel e shows the third cycle of the new algorithm. Here, the starting conformers are in wells E, H, and M. Conformers from well H would normally be discarded for being too close to a previous starting position, but this is still the best energy found so far, so this conformer is retained. As an aside, this step illustrates why it is important to wait for two cycles without improvement before terminating the algorithm rather than the single cycle without improvement that the algorithm in CREST uses. It is common, especially after a cycle which has resulted in a significant improvement in energy, that few of the conformers generated in that cycle are low enough in energy to be selected as starting points, and so the next cycle may not find a lower-energy conformer, even as it does find conformers that will eventually lead to better energies. The other wells with acceptable energy to RMSD ratios and sufficient distance from previous starts in this cycle are E and M. The third cycle finds the absolute minimum in well C, and after two additional cycles, the algorithm will terminate, having failed to find a lower-energy conformer.