Our ABFE and RBFE protocols are optimized in such a way that they provide high efficiencies for the calculations by making use of large distributed computational resources. Specifically, the non-equilibrium (NES) free energy calculations implemented in our thermodynamic cycles are suited for parallelization over large distributed computing resources. We have calculated the RBFEs of ligand transformations and ABFEs of trapped waters in 105 ns (30 ns for equilibrium and 75 ns for the NES free energy calculations) and 109 ns (84 ns for equilibrium and 25 ns for the NES free energy calculations) simulation times per calculation, respectively. In principle, the RBFE protocol studied here can be made even more efficient by decoupling the trapped water and transforming the ligand simultaneously in a single NES free energy calculation. In our current protocol, we combine equilibrium simulations, to apply and remove the restraints, with NES simulations, to decouple the trapped water and transform the ligand. We do not necessarily see this particular combination of choices as critical for our protocol. All equilibrium simulations in our protocol are run in parallel, so they do not increase the time to solution. Moreover, NES simulations require drawing starting structures from the equilibrium simulations, making the equilibrium simulations necessary.