For the targets, TYK2 and Thrombin, we obtain a good overlap between the grown Rgroups and the crystal structures. In the former case, the dihedral angle formed between the grown cyclopropyl C2 and C3 carbons and the amide carbonyl oxygen core (30 • and -37 • ) are in agreement with those reported experimentally. For Thrombin, although the added R-group here is a rigid phenyl moiety, we make use of the option to add atoms from the core to the flexible region and allow the linking -CH 2 -group to freely rotate during structural optimisation. This added flexibility leads to a rotation of the phenyl group of less than 10 • , compared to the corresponding crystal structure. The P38 benchmark set includes a series of alkyl amino substitutions originally investigated as part of a structure-activity relationship study into kinase inhibitors. Here, the added amino group is correctly positioned to form a hydrogen bond with the protein backbone, though the i-Pr group is rotated by around 60 • compared to the crystal structure (Figure (c)). In PTP1B, the grown cyclohexyl substituent is able to rotate quite freely, with many conformations predicted to lie within 5 kcal/mol of the minimum. The minimum energy structure shows good overlap with the crystal structure, 60 but connects to the core at the axial position of the cyclohexyl group (Figure ). In this case, the core structure contains a Br atom, so we are unable to optimise with the ANI2x potential (the workflow defaults to the Parsley force field for the ligand). Interestingly, if we remove the Br atom, and re-run the workflow using hybrid ML/MM optimisation, we recover the equatorial connection as the lowest energy conformer, in agreement with the crystal structure (Figure ). This demonstrates the potential advantages of employing hybrid ML/MM structure prediction methods in binding mode determination.