Enzymatic nucleophilic substitution reactions are ubiquitous as key steps in biochemical processes of living cells. Despite their importance, they are poorly understood, in particular regarding the exact mechanism and involvement of the protein environment and the role and mechanistic involvement of metal ions. Through interpretative methods from chemical reactivity theory, I will tackle the missing links in this field of molecular life sciences. This project thus goes beyond transition state calculations, which are today’s state of the art in computational enzymology, by addressing the question why. The project’s goal is to build a new research protocol to give insight in enzymatic reactions. This is original and innovative, and will as such contribute to Europe’s excellence. Through the integrated scientific and complementary skills training, it will offer much to my career development.The role of metal ions and the protein environment in triphosphate hydrolysis and sulfur oxidation reactions, which are abundant and ubiquitous enzymatic reactions involved in e.g. signal and energy transduction will be untangled via quantitative molecular orbital (MO)-theory. The MO-model and its associated energy-decomposition approach, for which the host will offer a training, can make trends in reaction barriers transparent and is the current state of the art in explanatory chemistry. This approach is only marginally used to tackle the chemistry of enzymatic reactions and gives the project its originality and pioneering nature. Further, by studying the nature of the reaction barrier of sulfur oxidation reactions, I will pioneer the field of theoretical redox protein sulfur chemistry. Sulfur redox biology is being studied extensively by biochemists, but only marginally by theoreticians.In conclusion, by studying representative proteins, this project translates fundamental chemical insights into biological relevance, giving the project its interdisciplinary nature.