Notably, the protein-ligand system (TYK2-ejm complex) exhibited greater timestep resilience than small-molecule transformations, with only 60% of 4 fs comparisons showing significant dU/dλ deviations (Table ). This suggests possible inherent damping effects in protein environments, potentially from restricted ligand mobility or attenuated high-frequency motions in binding pockets. On the other hand, aqueous-phase simulations displayed heightened sensitivity, where 100% of 4 fs timestep comparisons differed significantly from 0.5 fs references. Such system-dependent behavior necessitates tailored timestep selection criteria rather than universal guidelines, particularly for charge-dominated transformations like cAMP→Rp-cAMPS versus nonpolar systems such as ethane→ethanol.