To help understand the need for modifications to CREST for the problems of interest, it is important to understand the mechanics of CREST and the options available within CREST for the exploration of the conformational space of dimers and n-mers. The RMSD biasing within CREST is controlled by two parameters, kpush and alpha, which control the energetics of the biasing and the width of the Gaussian bias potential, respectively. Units are E h (Hartree) for kpush and Bohr -2 for alpha. A default run of CREST performs 14 MTD runs in the first cycle, and 12 in each subsequent cycle. Within each cycle, each MTD run has its own combination of kpush and alpha. The screening is done in an iterative fashion, starting from very loose geometry convergence thresholds, and proceeding to tighter ones, discarding the highest-energy conformers along the way. When one such cycle has been completed, CREST starts a new cycle from the best (i.e., lowest-energy) conformer found in the previous cycle. All conformers found in any cycle are retained and used in the final ensemble, as long as they are within the low-energy window (default: 6 kcal/mol above the best conformer, i.e., that which is lowest in energy). When there is no improvement from one cycle to the next, CREST runs molecular dynamics (MD) starting from the four lowest-energy conformers and runs a genetic crossing algorithm to search for more diverse conformers. Genetic crossing exchanges motifs found in parts of one conformer with those from another conformer, potentially increasing the volume available to sampling, but as currently available in CREST, it only works as intended for single molecules, not for clusters.