The conformers presented in this example come from the third cycle of the geometry search for the heterodimer of model compounds 1 and 2a. Panel a shows the threshold selection criteria as the green shaded area, while panel b shows the quotient selection criterion in Figure illustrates the improved algorithm for ensemble generation for clusters of highly flexible molecules. Four MTD runs are performed at each geometry, one with each combination of kpush and alpha of the reduced settings (vide supra). This weaker biasing still encourages the exploration of unvisited conformations but is more likely to retain the important non-covalent interactions while it does so. Once the MTD runs are complete, the four trajectories for each structure are combined and screened using the screen function of CREST. Each conformer in the resulting ensembles is then compared to the starting structure of the MTD run from which it originated using the rmsd function of CREST. For each conformer, the ratio of relative energy (in kcal/mol) to RMSD (in Å) is calculated. To select conformers for the next cycle, all conformers from a cycle are ranked by energy, relative to the lowest energy found. The lowest energy conformer is carried forward, along with up to 11 conformers for which this ratio is less than 0.5 kcal mol -1 Å-1 , subject to the requirement that they are at least 1 Å in RMSD from each other and from all structures which have been used as starting points in previous cycles. If a conformer does overlap with a previously selected conformer (as judged by RMSD), then the next highest in energy is selected, until 11 have been selected, or until the list of conformers with an energy to RMSD ratio less than 0.5 kcal mol -1 Å-1 is exhausted. This approach ensures that a wide range of starting points are used, thus exploring a much greater portion of configuration space than if only the lowest-energy conformer was used, while still prioritizing low energy starting points. If there is no improvement in the lowest-energy conformer for two successive cycles, then the algorithm terminates. All conformers found in all cycles are then collected and resorted using the cregen function of CREST to produce a final ensemble. This cycle starts from the lowest-energy conformer found in the first cycle, which is located in potential well H. This cycle does not find a better conformer than that in potential well H, so CREST terminates. Panels c through e illustrate the modified algorithm. In panel c, the run is initiated from the same potential well, I, as in the run using the iMTD algorithm of CREST. While the weaker RMSD biasing keeps the simulation on the low-energy portion of the potential energy surface longer, it also has a reduced capability to force the MTD runs to explore new regions of the potential energy surface. In addition, fewer MTD runs (four vs fourteen) per starting point are used, to balance the higher number of starting points.