For significantly larger ligands, exemplified by the "LIDS" data set assembled for this work, we are able to obtain tightly converged results in some cases but two metalloenzymes prove to be problematic due to the presence of Zn 2+ near the ligand binding site. In these cases, we were unable to obtain results that were converged to sub-kcal/mol accuracy at reasonable cost. However, if the intent of these calculations is to generate ab initio data sets for ML approaches, then there is some question as to whether sub-kcal/mol accuracy is a reasonable standard given significant disparities between ∆E int (computed for a single binding pose) and ∆G • bind . Although further testing is needed, the protocols developed here may already be sufficiently accurate to generate ab initio training data that do not rely on experimental inhibition constants, thus can be trusted for novel ligands that do not resemble existing drugs.