masterThesis
Análise bioquímica quântica do regulador TtgR e seus efetores
Fecha
2019-05-10Registro en:
MATIAS, Érika Geicianny de Carvalho. Análise bioquímica quântica do regulador TtgR e seus efetores. 2019. 68f. Dissertação (Mestrado em Ciências Biológicas) - Centro de Biociências, Universidade Federal do Rio Grande do Norte, Natal, 2019.
Autor
Matias, Érika Geicianny de Carvalho
Resumen
The problem of cross-resistance to different classes of MDR (multidrug resistance) antibiotic
has become a routine event in current medicine, implying therapeutic failure. Efflux pumps
collaborate considerably for this resistance to antibacterial agents, the expression of such
mechanisms is controlled by transcriptional regulators. TtgR is a multidrug binding regulator
of the TtgABC pump, present in P. putida, it exhibits strong similarity to QacR, a multiple
drug binding protein of S. aureus. We show here three crystallographic structures of TtgR,
DOT strain T1E, in complex with the flavonoid Quercetin (QUE) and with the antibiotics
Tetracycline (TAC) and Chloramphenicol (CLM). Through data with crystalline structures
and computational simulations, it was possible to analyze the energetic contributions of these
effectors to the general bonding site of TtgR using the Functional Density Theory (DFT) and
the Molecular Fractionation Method with Conjugated Layers (MFCC). The results showed
the energetic values of each amino acid residue constituting the interaction pocket with the
ligands under analysis. This evaluation occurred within a radius of up to 13.0 Å away from
the drugs. These effectors couple to the TtgR protein in a similar way, sharing a hydrophobic
core, such as: LEU93, LEU92, ILE141, VAL171 and VAL96. It was observed some specific
interactions with polar amino acids, such as ARG176, which became important for the TtgRQUE and TtgR-TAC complexes and HIS70 for the TtgR-TAC and TtgR-CLM complexes.
This energetic characterization provides us with information relevant to understanding MDR
resistance, concomitant with new possibilities in drug planning versus this mechanism of
resistance.