The accurate prediction of protein-ligand binding free energies is a central goal of computational chemistry, with key applications in early stage drug discovery. However, calculations of protein-ligand binding thermodynamics still involve a number of challenging choices, including the choice of empirical force field, specifying the protonation states of ionizable residues, adding hydrogens and otherwise adjusting the initial protein structure, and positioning the candidate ligand in the binding pocket. Predictions of protein-ligand absolute binding free energies have achieved root mean square errors around 1-2 kcal/mol for "wellbehaved" systems , with deviations an order of magnitude larger for some protein families with slow degrees of freedom . Retrospective relative free energy calculations on a series of congeneric ligands, using proprietary methods, have also achieved root mean square errors compared to experiment of around 1 kcal/mol . However, it is not possible to determine how much of the prediction error can be attributed to each of the decisions made by the modeler, as opposed to accuracy limitations of the force field.