Authors: P.H.S. de Bruin, M.Z.S. Flores, E.W.S. Caetano, B.S. Cavada and V.N. Freire
Affilation: Universidade Federal do Ceará, Brazil
Pages: 648 - 649
Keywords: TetR, tetracycline, DFT
Tetracyclines are a class of broad spectrum antibiotics whose use has been limited by the emergence of bacterial resistance. The most common mechanism of resistance is regulated by the repressor protein, TetR. The structure of the complex between 7-chloro-tetracycline (7ClTc) and TetR of class D (TetR) has been previously determined by X-ray diffraction. The binding site is composed primarily of fourteen residues. The goal of the present study is to analyze the ligand-protein interaction in the binding site. This analysis was made by successive Density Functional Theory (DFT) energy calculations. The calculations were performed using the Generalized Gradient Approximation (GGA) and the Becke-Li-Yang-Par hybrid functional (BLYP). We have obtained the bond energies between 7ClTc and each residue of the pocket, which revealed the key interactions of the binding site. Gln116, Met177, His64, Glu147 and His100 showed the strongest bond energies with 7ClTc and its attached Mg - waters complex. This matches almost perfectly with experimental data showing that these residues are essential to produce the necessary conformational rearrangements on TetR. Also, the mapping of the connections in the binding site is important to allow rational design of small molecules that would induce a TetR transcriptional regulator more effectively.