  We compute absolute binding affinities for two ligands bound to the FKBP
protein using non-equilibrium unbinding simulations. The methodology is
straight-forward, requiring little or no modification to many modern molecular
simulation packages. The approach makes use of a physical pathway, eliminating
the need for complicated alchemical decoupling schemes. Results of this study
are promising. For the ligands studied here the binding affinities are
typically estimated within less than 4.0 kJ/mol of the target values; and the
target values are within less than 1.0 kJ/mol of experiment. These results
suggest that non-equilibrium simulation could provide a simple and robust means
to estimate protein-ligand binding affinities.
