Molecular dynamics simulations to elucidate the aggregation mechanisms of the aldose-keto reductase protein in Trypanosoma cruzi

TRUJILLO, PABLO; ALVAREZ, G; ADUVIRI, SEBASTIAN; GARAVAGLIA, PA; ASCIUTTO E; CANNATA, JB; GARCIA, GA; PICKHOLZ, MONICA

La Plata

Congreso; XXXIV Reunión Anual de la Sociedad Argentina de Protozoología; 2023

Sociedad Argentina de Protozoologia

Chagas disease, caused by the protozoan Trypanosoma cruzi, is considered a neglected tropical disease and affects more than 7 million people in the Americas. The enzyme Aldo-keto reductase of T. cruzi (TcAKR) is a biological target of interest due to its potential involvement in the metabolism of trypanocidal drugs. Experimental kinetic studies demonstrated that TcAKR exhibits both aldoketo reductase (AKR) and quinone oxide reductase (QOR) activities, with hyperbolic kinetics and sigmoidal kinetics, respectively. In agreement with the sigmoidal kinetics, experimental techniques indicated that TcAKR can form oligomers. In this context, our goal was to obtain molecular information about the stability of the multimeric forms through computational molecular dynamics simulations (MD). To achieve this, we pursued two strategies. Firstly, we evaluated the stability of preassembled dimers, and secondly, we analyzed the temporal evolution of aggregation starting from eight TcAKR molecules sufficiently separated from each other. We discovered that TcAKR molecules are stable in dimeric forms and can also form stable supramolecular structures. In the case of supramolecular arrangements, we found a preferential motif where a central monomer interacts with three neighboring monomers. This arrangement is consistent with the formation of tetramers. Additionally, we identified key residues involved in the aggregation process and the structural characteristics that promote and stabilize the oligomers structure. These computational studies on the aggregation states of TcAKR can guide further experimental research and assist in the rational design of synthesis strategies that allow for the modulation of aggregation.