Dataset Compilation. A search was carried out in the Binding MOAD database, which is enriched for ligand-protein complexes with resolutions less than 2.5 Å extracted from the Protein Data Bank (PDB) . The cofactors with the highest frequency and a number of rotatable bonds greater than or equal to 15 were selected. Then, for each distinct number of rotatable bonds, the cofactor with the largest number of experimental structures was selected. This resulted in 7 different cofactors: Acetyl coenzyme A (ACO), Coenzyme A (COA), Flavin adenine dinucleotide (FAD), Nicotinamide adenine dinucleotide phosphate (NAP), Nicotinamide adenine dinucleotide (NAD), Guanosine 5'-triphosphate (GTP) and Adenosine 5'-triphosphate (ATP). The entries in the PDB for these cofactors were downloaded on November 27, 2023, where the number of entries per cofactor ranged from 190 (ACO) to 1956 (FAD). These entries were further filtered down by the following quality conditions: (i) PDB file with validation XML file available, (ii) a resolution of 2.5 Å or less, (iii) an average occupancy value of 1.0, (iv) all heavy atoms resolved, and (v) a real space correlation coefficient (RSCC) greater than or equal to 0.95. Multiple copies of a cofactor from the same PDB entry were included if they matched the above criteria. Covalent molecules were also included.