Thermodynamic integration to predict host-guest binding affinities

An alchemical free energy method with explicit solvent molecular dynamics simulations was applied as part of the blind prediction contest SAMPL3 to calculate binding free energies for seven guests to an acyclic cucurbit-[n]uril host. The predictions included determination of protonation states for both host and guests, docking pose generation, and binding free energy calculations using thermodynamic integration. We found a root mean square error (RMSE) of $$3.6\,\hbox{kcal}\,\hbox{mol}^{-1}$$ from the reference experimental results, with an R2 correlation of 0.51. The agreement with experiment for the largest contributor to this error, guest 6, is improved by $$1.7\,\hbox{kcal}\,\hbox{mol}^{-1}$$ when a periodicity-induced free energy correction is applied. The corrections for the other ligands were significantly smaller, and altogether the RMSE was reduced by $$0.4 \,\hbox{kcal}\,\hbox{mol}^{-1}$$. We link properties of the host-guest systems during simulation to errors in the computed free energies. Overall, we show that charged host-guest systems studied here, initialized in unconfirmed docking poses, present a challenge to accurate alchemical simulation methods.