Calculations of the absolute binding free energies show larger statistical uncertainties when compared to the relative free energy calculations (Fig ). The increase in statisti-cal errors arises due to larger perturbations to the system required by an alchemical absolute ∆G calculation. Coupling/decoupling of the whole ligand involves introducing/removing more interactions in comparison to the alchemical transformations of a small number of atoms when morphing ligands to one another for relative free energy estimations. Convergence of the absolute ∆G estimates in pharmaceutically relevant systems can be achieved, yet it requires extending the alchemical transitions to nanoseconds . Such slower transitions retain the system closer to equilibrium, dissipating less work along the alchemical path, thus facilitating convergence.