An alternative approach, employed throughout this work, is non-equilibrium switching (NES) . In this approach, one equilibrium simulation is run for each physical end state of a perturbation, after which many short non-equilibrium simulations ('transitions') are run during which the lambda value is continuously driven from one state to the other, and the free energy change is computed using thermodynamic integration . Whilst the overall simulation time per edge is identical to the equilibrium FEP approach, the transition simulations are independent, and therefore trivially parallelisable into many small jobs, allowing for routine evaluation of many edges simultaneously, even on a typical shared computing cluster.