Total energy drift increases with larger time steps in NVE ensemble of thermodynamic integration method Tables 3 and 4 detail the total energy drift observed in simulations of cAMP and ethane transformation systems across a range of timesteps: 0.5, 1, 2, 2.5, 3.333, and 4 fs. These data were acquired at five distinct λ values: 0, 0.25, 0.50, 0.75, and 1, employing both Hydrogen Mass Repartitioning (HMR) and SHAKE constraints to maintain system stability.