The RMSD bias causes the MTD runs to constantly explore spaces dissimilar to those which they have already visited, and then snapshots from the trajectory are screened for low-energy conformers. CREST gives excellent results for single molecules, or for clusters of small or rigid molecules, and has been used as a method of choice for conformational exploration of systems, partly because it frequently finds many more low-energy conformers than other stochastic methods. However, recent work 24 using CREST to explore dimers, trimers, and larger n-mers containing flexible monomers demonstrated the need for algorithmic improvements within CREST to locate the minimum energy structures. In that work, we reported on the structure and energetics of several dimers and trimers composed of asphaltene model compounds 1, 2a and 2b, with and without microhydration (i.e., +(H 2 O) x , where x=1-4). These are large, flexible molecules, with each molecule having 70-120 atoms and 6-16 rotat-able bonds, and having both hydrogen bonding and π -π stacking sites, see Figure . In the course of that work, it became evident that initial geometry explorations using CREST provided an insufficient sampling of the low-energy conformers of these systems. For example, an attempt to double-check the energy difference between two binding motifs of the trimer composed of two units of 1 and one of 2b (the 1 2 -2b trimer) demonstrated that the best conformer found by CREST depended strongly on the starting structure. That is, when two different conformers of this complex were used as input for a CREST run, the output geometries and energies were significantly different. In the double-checking case mentioned above, when started from a new initial structure, CREST found a conformer which was 14 kJ/mol lower in energy than anything that had been found to that point. Even starting two different CREST sampling runs from the same initial structure sometimes gave very different final results, with different lowest-energy structures having markedly different energies being found. Further investigations showed that for most of the molecular clusters under investigation, CREST had missed geometries substantially lower in energy than the lowest-energy structure it reported, demonstrating that a more thorough search algorithm was required.