The observed trade-offs between computational efficiency and thermodynamic accuracy present a dilemma for practitioners. While 4 fs timesteps offered ∼4× speedup over 1 fs simulations, they introduced errors (> 1 kcal/mol) that exceed typical chemical accuracy thresholds (1 kcal/mol) in free energy calculations. Our data suggest an optimal compromise at 2 fs, combining acceptable energy drift (< 1.5 kcal/mol/ns) with 2× efficiency gains relative to 1 fs simulations. For systems requiring ultra-precision with sub-kcal relative binding affinity, the 1 fs timestep remains preferable despite its computational cost.