Self-assembly of Trypanosoma cruzi aldo-keto reductase protein: Insights from simulations

TRUJILLO, PABLO; GARAVAGLIA, PATRICIA ANDREA; ASCIUTTO E; DOMENE, C; CANNATA, JOAQUÍN J B; GABRIELA ANDREA GARCIA; PICKHOLZ, MONICA

Congreso; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; 2021

Sociedad Argentina de Biofísica

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects a total of 6 millionpeople in the countries of the Americas. Particularly, in Argentine, about 1.5 millionpeople are infected and it is estimated that 30% of them will eventually developprogressive heart disease. Recent research suggests that the T. cruzi aldo-keto reductase(TcAKR) enzyme may be involved in the metabolism of action of trypanocidal drugs suchas Benznidazole (one of the drugs used to treat T. cruzi infection)1 and β-lapachone2. Onthe other hand, experimental kinetic studies demonstrated that TcAKR exhibits aldo-ketoreductase activity with Michaelian (hyperbolic) kinetics and quinone oxide reductaseactivity with sigmoidal kinetics. In agreement with the sigmoidal kinetics, differentexperimental techniques indicate that TcAKR is found as a monomer, dimer and tetramer3.In this work we used computer simulations to elucidate the possible aggregation of theTcAKR protein. In particular, through extensive Molecular Dynamics simulations ofoctamers, dimers and monomers, we found that the protein aggregates in supramolecular,such as dimers and tetramers. We were able to identify affinity regions (specificinteractions) between monomers as well as amino acid residues at the monomer interfacesthat stabilize the formation of supramolecular arrays of TcAKR. Furthermore, structuralstability was evaluated looking at the RMSD. We identified regions with higher mobility,mainly the last 30 residues at the C-terminus. The findings of self-aggregation capacity ofTcAKR could explain the differential kinetic behavior of the enzyme. Aggregation affectsboth the structure and dynamics of the system, suggesting that it would also affect thebinding of potential drugs.