One of the most robust stochastic methods for exploring conformational ensembles is the Conformer-Rotamer Ensemble Sampling Tool (CREST) program, 2 developed by the Grimme group. CREST relies heavily on the root mean squared deviation (RMSD) of atomic position between conformers. The RMSD is defined as the square root of the mean of the difference in coordinates for each atom in the molecule or cluster, relative to a given reference geometry -which is effectively the distance between the conformers in a 3N-6 dimensional Cartesian conformational space, where N is the number of atoms in the system. CREST uses an RMSD-biased form of metadynamics (MTD) and a semi-empirical GFNn-xTB (n=0,1,2) extended tight-binding approach to explore widely the conformational space of systems.