As previously argued the effect of the 3' downstream pro-Rp oxygen (with sulfur substitution 86% kcat decrease ) is most likely an indirect effect, where the 3' downstream pro-Rp oxygen increases the catalytic rate by correctly positioning the nucleophile. Another cause of the rate diminishing effect of the 3' downstream pro-Rp thio substitution is likely the hindered ability to stabilize a third metal ion (see MD section). Our QM/MM calculations explain all the aforementioned experimental evidence, evincing that H1126 is likely to act as the proton acceptor in contrast to previous calculations for which the conserved histidine was not included in the QM region.