Consequently, there is a need for rigorous uncertainty quantification for QM/MM calculations, i.e., to systematically assess the sensitivity of the QM/MM energy with respect to these technical choices and empirical parameters and to ultimately provide rigorous error bounds on the results of QM/MM calculations (compared to a full QM treatment). Mathematical and computational tools for quantifying uncertainties in computer simulations have been developed intensively in the past decades (for textbooks, see, e.g. Refs. 34,35) and are employed in many areas of simulation science, but their application is just starting to emerge in computational chemistry. Recently, we have applied such tools for analyzing the sensitivity of calculated spectra with respect to distortions of the molecular structure. Here, we aim at taking a first step towards uncertainty quantification for QM/MM methods by analyzing the sensitivity of QM/MM reaction energies with respect to variations of the MM point charges. While there are other relevant empirical parameters entering in QM/MM calculations, most importantly those related to the treatment of the QM-MM boundary (e.g., to the placement of the link atoms), we expect the MM charges to be a key factor influencing the final QM/MM results.