To run these at scale in a massively parallel fashion restricts the types of sampling methods that can be used. While great success has been shown with replica exchange methods to estimate binding free energies, such methods require communication across GPUs, as each replica must communicate with the others to enable swapping and appropriate mixing of alchemical states. . Replica exchange offers a powerful baseline to ensure that an alchemical transformation can be studied, and provides reasonable estimates, even for expensive mutational transformations .