In BLUES the alchemicalfactory module of openmmtools 89 version 0.11.2 was used to allow annihilation and restoration of toluene's steric and electrostatic interactions. The MD portions of these simulations used OpenMM's Langevin integrator. The NCMC portion of the OpenMM simulations used an implementation of the BAOAB integrator of Langevin dynamics During the NCMC propagation phase, we also froze the positions of protein residues further than 5Å from the ligand, and solvent molecules (which in this system were always more distant than 5Å from the ligand, to reduce the variance in work over the course of the NCMC protocol, thereby improving acceptance probabilities. The selection of the frozen water and protein residues was not updated during the simulation; this was appropriate in this case as the binding site is a buried, non-polar binding site with no water nearby and the ligands remain stably in the binding site, so no updates were needed. The long range dispersion correction was turned off during the NCMC integration steps due to computational costs recalculating the correction while scaling , but was accounted for by taking into account the differences in energy between the alchemical and normal systems at the initial and final states.