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Computational Study of the mechanism of conversion of ATP to cyclic-AMP catalyzed by the Edema Factor of Anthrax

Grant number: 13/22360-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2014
Effective date (End): April 30, 2018
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Physical-Chemistry
Principal researcher:Leandro Martinez
Grantee:Gabriel Ernesto Jara
Home Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:13/08293-7 - CCES - Center for Computational Engineering and Sciences, AP.CEPID


The Edema Factor (EF) is one of three major toxins involved in the disruption of cellular functions resulting from infection of a host organism by Anthrax. The EF is an enzyme that catalyzes the production of cyclic-AMP (cAMP) from ATP , known as Adenylyl cyclases . In eukaryotes, cAMP is a key signaling molecules and the infection by EF induces its overproduction, leading to cell death. Consistent with this mechanism, the EF gene defects cause reduction in virulence of the bacterium anthrax. Likewise, other pathogens such as Bordetella petrussis responsible for Pertussis, or Yersina pestis, which causes bubonic plague, also have similar edema factors. The mammalian Adenylyl cyclases catalyze the same reaction. However, these proteins exhibit little structural homology with the anthrax EF. Several structures of the EF of Anthrax were obtained, which allow a qualitative analysis of possible reaction pathways. On the other hand, these same structures are not conclusive about fundamental aspects of the catalytic mechanism, as the reactive conformation of the ATP, the number and mode of coordination of the ions of the active site, and the amino acids which are directly involved in the transfer of protons along the reaction.This project goal is to propose the most plausible mechanism for the reaction by computing the free energy surfaces involved in each plausible reaction coordinate. For this, the study of the mechanism of the reaction will be performed using quantum mechanics/molecular mechanics simulations (QM/MM).This work will be conducted at the Institute of Chemistry, UNICAMP under the supervision of Prof. Leandro Martínez, who has experience in the study of biological systems by classical molecular dynamics with conventional and non-conventional methods, in particular the Edema factor of Anthrax. In previous studies, classical MD simulations were used to probe the stability of the active site of EF, and the mechanisms of substrate and product dissociation as a function of the number of ions and the substrate conformations observed in crystal structures. Now, the catalytic mechanism will be probed, by taking advantage of the applicant's experience in hybrid QM/MM molecular dynamics simulations, obtained in his current postdoctoral project at the Modeling Group of the Faculty of Exact and Natural Sciences of the University of Buenos Aires, under the supervision of Doctors Marcelo Martí and Dario Estrin.Therefore, the Prof. Martínez's group will benefit from the experience of the candidate in techniques that are novel for the group, and the project will advance in the comprehension of an important biological problem in which the group has established expertise.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE OLIVEIRA, IVAN PIRES; LESCANO, CAROLINE HONAISER; DE NUCCI, GILBERTO. In Silico Mapping of Essential Residues in the Catalytic Domain of PDE5 Responsible for Stabilization of Its Commercial Inhibitors. SCIENTIA PHARMACEUTICA, v. 87, n. 4 DEC 2019. Web of Science Citations: 0.
DE OLIVEIRA, IVAN PIRES; JARA, GABRIEL ERNESTO; MARTINEZ, LEANDRO. Molecular mechanism of activation of Burkholderia cepacia lipase at aqueous-organic interfaces. Physical Chemistry Chemical Physics, v. 19, n. 46, p. 31499-31507, DEC 14 2017. Web of Science Citations: 2.
JARA, GABRIEL E.; MARTINEZ, LEANDRO. Anthrax Edema Factor: An Ion-Adaptive Mechanism of Catalysis with Increased Transition-State Conformational Flexibility. Journal of Physical Chemistry B, v. 120, n. 27, p. 6504-6514, JUL 14 2016. Web of Science Citations: 1.

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