Our simulations were run across several high performance computers including Summit at the Oak Ridge National Laboratory (ORNL) and SuperMUC-NG at the Leibniz Super Computing Centre. The performance of OpenMM and NAMD3 can be compared simply using the same hardware and for example running on one Nvidia V100 GPU with a ligandprotein complex of 35k atoms we see simulation speeds of 115 ns/day and 123 ns/day using OpenMM and NAMD3 respectively. Therefore, a TIES calculation with this system using 1 2 13 alchemical windows and 5 replica simulations per window takes around 70 minutes of wall time using 65 V100s. In this work NAMD2 is run on the CPU platform and using 96 Xenon Skylake cores the simulation speed is 26 ns/day. Therefore, using NAMD2 and 6240 cores for one TIES calculation, again with 13 windows and 5 replicas, takes around 5-6 hours of wall time. In OpenMM the calculation of potentials and gradients, required for FEP and TI analysis, can be performed concurrently with the simulation, this creates an overhead of around 10% in TIES MD. The speed of OpenMM without this overhead is therefore 127 ns/day. For our NAMD calculations either the potential or gradient can be saved with the simulation but not both. Therefore the TI and FEP results cannot be collected concurrently and a post-processing step is needed to extract the FEP result from the NAMD trajectories. This post-processing generally takes 10-20 minutes for one TIES calculation. More details of the alchemical protocol will follow here; for the precise details of the MD package settings and performance refer to sections 6-8 of the Supplementary Information.