The partial charge variations observed here may be remedied by using conformer-independent charges or by investing more research into determining how to unambiguously assign reliable charges regardless of input conformer. Otherwise, what is essentially noise can be triggered by variations in user input conformations, conformer-generation engine, or even choice of compute hardware, impeding the reproducibility of binding free energy calculations even when done with the "same" force field, method, and tools, thus adversely a ecting both predictive accuracy and method development and testing.