Molecular Dynamics Studies of Tripanosoma cruzi Trans Sialidase and T. Rangeli Sialidase mutants at the Covalent Intermediate Stage

DIEGO ALONSO DE ARMIÑO; LEZAMA, GUY; DARÍO A. ESTRIN; ALVAREZ, ROSA MARÍA S.; ADRIÁN ROITBERG

Villa Carlos Paz

Congreso; XLII Reunión Anual de la Sociedad Argentina de Biofísica; 2013

Sociedad Argentina de Biofísica

Molecular Dynamics Studies of Trypanosoma cruzi Trans Sialidase and T. rangeli Sialidase Mutants at the Covalent Intermediate Stage. Diego J. Alonso de Armiñoa, Guy Lezamaa, Darío Estrinb, R. M. S. Alvareza, Adrian E. Roitbergc a. Instituto Superior de Investigaciones Biológicas, INSIBIO (CONICET-UNT). Chacabuco 461, San Miguel de Tucumán, Tucumán, Argentina. b. Instituto de Quimica Fisica de los Materiales, Medioambiente y Energía, INQUIMAE-CONICET, Ciudad Universitaria, Pab 2, C1428EHA, Buenos Aires, Argentina. c. Quantum Theory Project and Departament of Chemistry, University of Florida, Gainesville, Florida, United Status of America. Trypanosoma cruzi is the causative agent of Chagas´ disease. T. cruzi trans-sialidase (TcTS) was shown to be an important factor in the microorganism´s virulence, and has been proposed as a target for drug design, a goal that requires a thorough understanding of the enzyme´s mechanism. Evidence indicates that the catalytic mechanism involves a long-lived covalent intermediate (CI), which is later attacked by an acceptor glycoconjugate, completing the sialic acid transfer. A key question is thus, how does TcTS protect the CI from hydrolysis until the acceptor glycoconjugate can position itself in the active site for the transfer reaction to take place. Previous works suggested the existence of a new switch mechanism sensitive to lactose, which deactivates the enzyme in abscence of acceptor ligand at the CI stage. Here we present new in silico studies in which we discuss the structural and sequence differences between TcTS and TrSA responsible for it.