Setup for ϵ-HREX. We scaled down the LJ parameters which, combined with Hamiltonian Replica Exchange (HREX), can enhance the sampling of slow degrees of freedom, as has been shown in the implementation REST2. Instead of running different replicas at different temperatures as in temperature replica exchange, all replicas are run at the same temperature while the potential energy of every replica is scaled differently. This can lead to an increase in the "effective" temperature of the system in the region where the interactions are being scaled and it was shown that this can improve the sampling efficiency compared to actual temperature replica exchange. Both nonbonded and bonded pa-rameters can be scaled down to enhance the sampling, however, here we only scale down the LJ-ϵ parameters of the ligands since we found that this was sufficient to improve sampling in most systems. In some cases we additionally scaled down the force constant of dihedral angles in the ligand to enhance slow rotamer sampling (see Section 5.4). We will refer to this protocol, as it modifies the LJ-ϵ and performs HREX, as ϵ-HREX throughout this work. The LJ potential, V LJ (r), is defined using an ϵ and a σ parameter