Simulations for groups 1 and 2 were based on the initial x-ray crystal structures with PDB codes 5ter and 4mfb, respectively. The proteins were truncated and underwent parameterization using the QUBE force field (Supporting Methods). ONETEP calculations were performed to obtain the ground state electron density, atomic charges and atomic volumes, in the same way as the ligands, as previously described. To facilitate set-up of QUBE simulations for proteins, the software QUBEKit-pro has been developed and is used here to generate OpenMM xml files from pdb and ONETEP output files. Using QUBEKit as a base has the advantage that most features can be easily applied to the protein, allowing for charge checking and symmetrization, for example.