The ESMACS simulations for the compounds S01 -S20 were initially conducted using 10replica ensembles on the DNAnexus platform () which provides strong cybersecurity. Previous studies have stablished a standard ESMACS protocol with 25 replicas, and shown that the combination of the simulation length and the size of the ensemble provides a trade-off between computational cost and precision. The choice of a smaller number here was designed to reduce computational cost on the cloud environment. The study was later extended to include two more compounds, C01 and C28 from Su et al. , renamed as S21 and S22, to extend ESMACS to 25 replicas and, more importantly, to perform TIES studies on the selected compound pairs. The Blue Waters supercomputer at the National Center for Supercomputing Applications (NCSA) in the US was used for the extended ESMACS simulations. The SuperMUC supercomputer at Leibniz Supercomputing Centre in Germany was used for the TIES simulations.