Modelling, Molecular Dynamics and Potential Antimicrobials of the Twin-arginine translocation system TatBC3

Abstract

The Twin-arginine translocation (Tat) system is a protein translocation system found only within bacterial and plant-based organisms that provides the ability to export prefolded proteins across membranes. This property makes the Tat system vital for the survival and virulence of bacterial organisms. Using a variety of computation methods including Molecular Dynamics Simulations, Protein and Molecular Docking, Molecule Imaging and Pharmacophore manipulation a TatBC3 protein complex was studied within an experimentally accurate Phosphatidylethanolamine-Phosphatidylglycerol (POPE/POPG) phospholipid bilayer. The methodology devised for use within this study utilizing protein docking tools was not able to produce functional TatBC3 models, therefore a model produced by a previous study (Alcock, 2016) produced using homology methods was used for simulation. When comparing POPC (Phosphatidylethanolamine) with POPE/POPG lipid bilayers in simulation is was found that the prior produced greater degrees of stability. Multiple Tat signal peptides (including mutants) were docked to the TatBC3 inner cavity, as expected non-mutant Tat signal peptides possessed a higher degree of binding affinity to the TatBC3 cavity. Interestingly Tat signal peptide mutants substituting an arginine residue within the highly conserved motif did possess a higher binding affinity than that of other Tat signal peptide mutants and even some non-mutant tat signal peptides. The inner cavity binding site and docked signal peptides were used for pharmacophore search. This revealed 15 commercially available molecules that could potentially function as novel antibiotics targeting the Twin-arginine translocation TatBC3 translocon.

Date of Award	28 Sept 2022
Original language	English
Awarding Institution	Coventry University
Supervisor	Sharon Williams (Supervisor)