To determine the global minima for each molecule, we employed a root-mean-square deviation (RMSD) matrix to compare the conformations generated by the conformation search engines with the lowest-energy QM conformation. The RMSD values for all conformations can be found in the SI specifically Table -S102. The conformations were ranked based on both RMSD and energy values, and those achieving the top rank (ranked as 1, lowest RMSD, lowest energy) in both categories were considered global minima and are highlighted in bold in Table . On the other hand, if the lowest-energy conformation did not correspond to the lowest RMSD value, it indicated that the engines failed to identify the global minima, and these instances are not highlighted. For instance, in the case of carnosine, Auto3D successfully identified the global minima with a rank of 1 out of 13 conformations, while ETKDG achieved a rank of 1 out of 9 conformations. However, CREST and Balloon were unable to find the global minima, as their lowest RMSD conformations ranked 7 out of 7 and 6 out of 10 in terms of energy, respectively. The details of the RMSD values, relative energies, and corresponding rank of Carnosine conformations are given in Table . It is important to note that the range of relative energies obtained from the conformation generation engines exhibits significant variation. Our analysis revealed that the relative energies generated by Auto3D span a wide range, while the relative energies produced by CREST are relatively compressed. For the carnosine system, all seven conformations generated by CREST exhibited relative energies within 5 kcal/mol, whereas none of the 13 conformations generated by Auto3D fell within this range. Notably, Conformation 9 (viz. Conf_9) was the second lowest in energy among the Auto3D conformations, but it had a higher energy by 15.9 kcal/mol. The highest relative energies obtained from Balloon and ETKDG were 6.3 kcal/mol and 17.8 kcal/mol, respectively. In comparison, the highest energy conformations generated by Auto3D and CREST were 31.9 kcal/mol and 5.7 kcal/mol, respectively. Detailed energy values for all the molecules can be found in the Supporting Information (Table -S102). Out of the 20 metabolites considered in this study, Auto3D successfully identified the global minima for 8 metabolites, whereas CREST detected them for 4 metabolites. Balloon and ETKDG each demonstrated success for 3 metabolites. The success rate of Auto3D in finding global minima was 40%, while CREST attained 20%. Balloon and ETKDG both achieved a 15% success rate, indicating comparatively lower performance.