Figure : Hardware di erences e ects on partial charge generation. Di erences in hardware result in di erent amounts of variation in assigned partial charges given the same input conformer. Each box and whisker plot represents the maximal partial charge di erence seen between the same starting conformer charged on an Intel processor and an M1 Mac using the specified charging method -AmberTools AM1-BCC or OpenEye AM1-BCC. (a) On average, using AmberTools AM1-BCC charges, the maximal absolute value of the partial charge di erence between the same starting conformer charged on the Intel processor and an M1 Mac was nearly 0, but there were instances of di erences up to 0.09 e. (b) On average, using OpenEye AM1-BCC charges, the absolute maximal partial charge di erence between the same starting conformer charged on Intel processor and an M1 Mac was nearly 0, but there were instances of di erences up to 0.03 e. For each conformer, we generated partial charges on an Intel processor and an M1 Mac. We ran 2 AHFE calculations for each conformer where the only di erence between the calculations was the partial charges, either from the Intel processor or M1 Mac. Di erences in hardware result in di erent partial charges given the exact same input conformer. These di erences can result in up to 3.8 ± 0.1 kcal/mol di erences in calculated AHFE. We note that each conformer only has one repeat per hardware environment used to generate those partial charges. We find that on the timescales simulated in this paper, our free energy estimates from a single partial charge set seem to converge to similar values (SI Figure ). On the other hand, free energy estimates from di erent partial charge sets results converge to di erent values (Figure ) .