In the following analysis, benzene-grafted perturbations will be referred to as RBFE-Space perturbations, whereas the template perturbation (i.e. with the original ligand scaffolds) will be referred to as drug-like perturbations. Drug-like solvated SEM values correlate well (R=0.86) with their bound counterparts, but tend to show lower magnitude (figure ). This is surprising as a bound system has higher complexity than a solvated box -it is expected however that the short sampling time for this analysis (1-ns/λ ) was insufficient to relax the protein topology in the simulation, thus enforcing a relatively rigid environment for the ligand perturbation in which only a narrow range of conformations could be sampled. This was deemed acceptable for the present study as we are mainly interested in correlating SEM values. RBFE-Space SEM values also correlate well to both drug-like solvated, bound SEM values (R=0.74 and 0.87, resp.) and to ∆∆G SEM values (R=0.75); A trend in the number of heavy atoms perturbed increasing with higher SEM values can be observed which reflects the trend seen in figure . It should be noted that in this prototypical version of RBFE-Space there is a possibility that R-groups that are separated from each other in the context of a drug-like scaffold will interact with each other when grafted onto a benzene scaffold. We have observed a trend for greater deviation between RBFE-Space and ligand SEM values for cases where bulky R-groups are being simultaneously grown and vanished in the same perturbation. Although not investigated in depth, this issue is assumed to be present in a small population of RBFE-Space, and will have to be resolved in future versions of the dataset. Early solutions to this problem could for instance be placing the second R-group on the para aromatic carbon of the benzene scaffold; however any third (or more) R-groups will reintroduce the issue. Alternatively, larger scaffolds could be explored. The main objective of this analysis is to assess whether the RBFE-Space placeholders' SEM values sufficiently correlate to ∆∆G bind SEM values of their drug-like counterparts (figure ). Although only moderate correlation has been reached, we postulate that this is a logical effect of simplifying ligand perturbations by grafting them onto a common benzene scaffold. Such simplification was made here to obtain a training domain that is transferable to a variety of congeneric series. Through this simplification, several sources of information are discarded: 1) removal of protein topology and ligand-protein interactions 2) removal of ligand scaffold (interacting with protein or solvent) 3) reduced sampling time (1-ns/λ instead of 4-ns/λ ). Whereas all of these could be included in RBFE-Space they would require a significant increase in the size of the training domain to enable development of transferable models.