Several approaches have yielded accurate predictions for large scale RBFE calculations. Equilibrium free energy perturbation (FEP) calculations, popularised by Schrodinger's FEP+ workflow, employ discrete windows along the alchemical coordinate (usually denoted lambda) for a step-wise morphing from one compound to the other . Individual simulations at discrete lambda states (typically 12-24 states depending on ligand similarity and charge state changes) can be run in parallel and employ REST-type enhanced sampling between replicas .