Having established the accuracy of BespokeFit torsion parameters in gas phase scans, we now move on to computing (as a proof-of-principle) the relative binding free energies of the TYK2 series using the base Parsley FF, and two of our bespoke augmented FFs, namely BespokeFit (GFN2-xTB) and BespokeFit (B3LYP-D3BJ/DZVP) from Table . This protein target was chosen as a system for which conventional force fields tend to perform well , and so sampling issues are unlikely to affect the interpretation of the data. The fragment FFs were first combined into a single FF, which can be used to parametrize all molecules in the set using the FF combiner CLI tool of BespokeFit. Relative binding free energies were calculated using a workflow based on pmx , which is described in Supporting Information Section S1.3.