Ensembles of NAMD simulations with 25 replicas were performed, with different initial velocities drawn independently from a Maxwell-Boltzmann distribution. A series of equilibration runs, totalling 2 ns, were conducted, with the restraints on heavy atoms gradually removed. Finally, 4 ns production simulations were run for each replica for all ESMACS and TIES simulations. For the ESMACS free energy calculations, the conformations of the protein and the ligands were extracted from the complex simulations.