Computational techniques for estimating relative differences in protein-ligand binding free energy have now reached remarkable accuracy. Relative binding free energy calculations over a large range of protein-ligand complexes have shown average agreement with experiment to be within 1 kcal/mol (4.184 kJ/mol) . These methods have become mature and reliable enough to be included in industrial drug discovery and lead optimization pipelines . A substantial limitation of this approach, however, is the requirement for the ligands to be structurally similar to each other: the predictive power decreases for ligands with different scaffolds or binding poses. Evaluation of novel ligand classes, therefore, requires a prior experimental absolute binding free energy as a reference for each new class of mutually similar ligands. Thus, the next qualitative leap for the field of first principles based protein-ligand affinity estimation encompasses the reliable and accurate prediction of absolute binding free energies.