The trans-sialidase of Trypanosoma Cruzi (TcTS) has been identified as a potential target to fight the Chagas disease, which affects 16-18 million people in Latin America and lacks an effective cure. No effective inhibitor is known for TcTS. Therefore, a de tailed understanding of its mode of action and the associated energetics is of interest and could help the design of such an inhibitor. We propose to perform this study by computational means in tight collaboration with the crystallographic group in the Institute Pasteur (P. Alzari) to further exploit their data.
On the one hand, we will analyse the contribution of different residues and ligand moieties to the binding affinities. For that, it appears important to take ligand and enzyme relaxation, as well as explicit solvent molecules into account because the recently solved high- resolution crystal structures have revealed conformational switches along the reaction and flexibility of the active site. We will use a molecular dynamics-based free energy method recently developed in the Pasteur Institute group, which fulfils these requirements and has predicted mutation effects with similar accuracy as the experiment. Furthermore, we propose to analyse the binding properties of new molecules made up of moieties taken from known ligands in order to attempt to identify the combinations giving tighter binders.
This novel computational approach will, if successful, become a very valuable tool in other projects. On the other hand, we will study the chemical steps leading to the formation of a glycosyl-enzyme covalent intermediate allowing the trans-sialidase function whilst preventing the hydrolysis (sialidase function). A quantum mechanics/molecular mechanics potential will be used to understand how the enzyme forms this covalent intermediate and which proprieties of the ligand are important for this reaction. The results of this study will be useful to explore the design of a covalent inhibitor.
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