By minimizing the ambiguities involved in modeling protein-ligand complexes, host-guest systems offer a way to isolate and directly probe force field error. A variety of techniques for computing absolute binding free energies have been applied to host-guest systems, and some have shown accuracy as good as ~1 kcal/mol, as highlighted in the recent SAMPL5 and SAMPL6 blind challenges . The techniques applied to this problem have included both quantum and classical dynamics, employing a range of energy and solvation models, with some techniques having knowledge-based steps, docking, or clustering . The attach-pull-release (APR) method has consistently been ranked among the most reliable techniques for predicting binding thermodynamics of host-guest complexes in blind challenges . In APR, the reversible work of transferring the guest from the binding site to solution, via a physical pathway, is computed using a series of umbrella sampling windows. Simulating each window and integrating over the partial derivative of the restraint energy with respect to the restraint target, in each window, is used to generate a potential of mean force along the pulling coordinate, yielding the binding free energy at standard state, ΔG° after applying an analytic correction to account for the effective concentration of the guest during the simulation . Furthermore, subtracting the mean potential energies obtained from long simulations of the solvated bound complex and the solvated dissociated complex yields the binding enthalpy, ΔH . Together, ΔG° and ΔH can be combined to determine the binding entropy at standard state, ΔS°. Thus, APR provides the complete thermodynamic signature of a host-guest binding reaction: ΔG°, ΔH, and -TΔS°.