The free energy difference was obtained from simulation data using the MBAR estimator 59 as implemented in the alchemlyb/pymbar package. The first nanosecond of the 10 ns production run was discarded, as additional equilibration. In the TYK2, ERα and BACE1 systems, we ran three independent repeats to assess the convergence of the free energy estimate and to get an estimate of the uncertainty, though not in the MALT1 system to reduce compute costs and to get a better idea of typical production-level accuracy. In the MALT1 and BACE1 systems, absolute binding free energies were obtained from the ∆∆G values using a maximum likelihood estimator as implemented in the arsenic package (later renamed to cinnabar). That same package was used to generate correlation plots and the error and correlation statistics used in this paper.