Insights from the docking and molecular dynamics simulation of the Phosphopantetheinyl transferase (PptT) structural model from Mycobacterium tuberculosis

Abstract

A great challenge is posed to the treatment of tuberculosis due to the evolution of multidrug-resistant (MDR) and extensively drugresistant (XDR) strains of Mycobacterium tuberculosis in recent times. The complex cell envelope of the bacterium contains unusual structures of lipids which protects the bacterium from host enzymes and escape immune response. To overcome the drug resistance, targeting "drug targets" which have a critical role in growth and virulence factor is a novel approach for better tuberculosis treatment. The enzyme Phosphopantetheinyl transferase (PptT) is an attractive drug target as it is primarily involved in post translational modification of various types-I polyketide synthases and assembly of mycobactin, which is required for lipid virulence factors. Our in silico studies reported that the structural model of M.tuberculosis PptT characterizes the structure-function activity. The refinement of the model was carried out with molecular dynamics simulations and was analyzed with root mean square deviation (RMSD), and radius of gyration (Rg). This confirmed the structural behavior of PptT in dynamic system. Molecular docking with substrate coenzyme A (CoA) identified the binding pocket and key residues His93, Asp114 and Arg169 involved in PptT-CoA binding. In conclusion, our results show that the M.tuberculosis PptT model and critical CoA binding pocket initiate the inhibitor design of PptT towards tuberculosis treatment.

Keywords: I-TASSER; Molecular dynamics simulations; Mycobacterium tuberculosis; PptT.

Figure 1

Structural analysis results of M.tuberculosis PptT a) three dimensional model of PptT using ab-initio/threading method from I-TASSER server. Color scheme: Helices in red, strands in yellow and loops in green; b) Root means square deviation (RMSD) plot of PptT model from MD simulations of duration 10 ns in GROMACS. c) Radius of gyration (Rg) of PptT model from MD trajectory; d) PptT-CoA binding interaction from PatchDock based on molecular docking. CoA molecule represent in stick model and protein in cartoon model. Hydrogen bonds represented in pink dashed lines.