Focussing the computational microscope on the E. coli cell envelope: model development and simulation studies

The development of bacterial resistance to currently available antibiotics is a major problem for healthcare worldwide. The rational development of new therapeutics relies upon a detailed knowledge of how drugs and potential drug molecules interact with the membranes that surround and protect bacteria. Molecular dynamics is a computational tool that can be utilised to explore the time-dependent behaviour of biological systems, from single molecules to more complex multicomponent systems. To this end, I have employed coarse-grained molecular dynamics simulations for a range of studies that are presented in this thesis. Firstly, I develop different models of lipopolysaccharide (LPS), which are molecules found in the outer leaflet of the outer membrane of Gram-negative bacteria. Next, I use these models to explore the interaction of pristine carbon fullerenes (C60) with E. coli membranes at the molecular level. I predict that pristine C60 has a limited tendency to penetrate LPS leaflets in the presence of calcium ions at 310 K, but more readily penetrates LPS leaflets at higher temperatures and in the presence of sodium ions, or when small patches of palmitoyloleoylphosphoethanolamine (POPE) lipids are present within the LPS membranes. Lastly, I use these models for simulations that are designed to understand more general principles of molecular interaction between native membrane proteins and lipids in an E. coli cell envelope. The results revealed that the curvature and fluidity of membrane lipids are strongly influenced by the diffusion of proteins and, more specifically, that charged lipids are sequestered locally by the AcrBZ component of the AcrABZ-TolC complex of proteins