Transketolase catalytic reaction pathway. Study of thiamine diphosphate activation and complete catalytic cycle

The structural and reactional aspects of enzyme catalysis are intimately linked. Only one conformation of the enzyme-substrate interaction, the so-called reactive conformation, can lead to the catalytic reaction. It is on this basis that we carry out our reaction pathway studies using a mixed quantum/classical method, the strategy of which we present here, applied to the case of transketolase. We will describe how, starting from several crystallographic structures of transketolase available in the PDB and considering the results of various experiments described in the literature, we have succeeded in proposing a structure corresponding to an initial reactive state, and how we were able to simplify it to perform QM/MM calculations. The structural and energetic coherence of the reaction pathway will then depend on the relevance of the initial interaction model.