How can absolute binding free energies be calculated?

In the calculation of binding free energies, such as between a protein and a ligand, I learned that absolute values cannot be obtained from simulation (such as taught in [this lecture](https://dasher.wustl.edu/chem478/lectures/lecture-18.pdf), slide 2). Rather, with the appropriate reference state, only relative free energies can be calculated. However, there are a number of papers that discuss calculations of *absolute* free energies (ex. [recent JACS paper](http://pubs.acs.org/doi/pdf/10.1021/jacs.6b11467)). What does this mean? Are the absolute values--even among different papers--using some kind of general reference state?




Free energies are computed by transforming one state into another, e.g. by transforming ligand A into a ligand B (inside a protein in our case). This transformation yields the difference in binding free energies between ligands A and B: $\Delta \Delta G^{bind}\_{A \rightarrow B}$. This is a *relative* binding free energy.


On the other hand, if ligand A is transformed into nothing, it's *absolute* binding free energy is calculated: $ \Delta G^{bind}\_A$. 


In both cases ($\Delta G$ and $\Delta \Delta G$), we are calculating differences between two states, and never calculating the absolute free energy $G$ of a single state. This is probably what you meant by: "only relative free energies can be calculated."


PS: since binding occurs in a solvent, it would be necessary to take ligand solvation and protein solvation into account, in order to properly describe the unbound state. For example, in the calculation of $\Delta G^{bind}\_A$ described above, ligand A should appear in bulk water instead of disappearing completely.


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