As a practical consideration for our first proposal, the subdivision of ligands into smaller groups, each with 𝑛 ln(𝑛) edges, reduces costs while maintaining precision (Fig. ). There are additional costs if clusters do not have a suitable reference ligand. If a reference does not exist, either more experimental reference values need to be collected or an ABFE simulation performed. In addition, to aid users in increasing the number of edges per design, HiMap has a fully automated clustering algorithm (Software Methods). Clustering may be helpful because resources may limit the number of edges per design.