Novel Multidimensional Enzyme Reaction Dynamics method reported in ACS Catalysis
The suppression of competing reactions that lead to side products is one of the key mechanistic actions defining enzyme catalysis. The transfer of sialic acid (SA) in a water solution is susceptible to two competing side reactions, but a single product is the outcome in the glycosylation and deglycosylation steps of the trans-sialidase (TS) in the Trypanosoma cruzi (T. cruzi) parasite, generally known as TcTS. We use multidimensional QM/MM free energy computations to reveal a competition between a minor elimination reaction and the dominant displacement reaction present in both steps. The simultaneous monitoring of the progression of the competing reactions reveals lower barriers in the free energy profiles, a greater sampling of favorable reactant stereoelectronic alignments, and a greater number of possible transition paths leading to successful crossing reaction trajectories for the dominant displacement reactions in comparison with those of the elimination reactions.