Simulation studies of the bacterial periplasm.

Abstract

Given the current rise in antibiotic resistant bacteria, E. coli takes center stageas a bacteria that is used commonly as a model organism. Bacteria possess a complex, crowded cellular environment that appears to be chaotic and disordered at a first glance. Their cellular structure allows them to survive and adapt to harsh conditions and varied environments. Molecular dynamics is a widely used approach to study biomolecules in biological conditions. Using this the fine, atomic level details of the forces that hold these molecules together and as a sum drive biological function forward can be revealed. This enables the specific interactions of biological building blocks, such as proteins, lipids and other polymers, in the E. coli environment, to be studied. Chaperone proteins can transport small molecules in the cellular environment, where this is not limited to bacteria, such as in the case of human apolipoprotein D. Using a marriage of experimentally sourced data as an anchor to reality and approximations based on theory, the compartment of the bacteria known as the periplasm was studied. In Chapter 3 it was observed that Braun’s lipoprotein (BLP) acts as a staple that bends and tilts and can interact with outer membrane protein A (OmpA) and the cell wall. This was extended to a full periplasm, in Chapter 4, where BLP interacts with the cell wall in the presence of OmpA and TolR. In this it was shown that TolR and OmpA can bind with the cell wall simultaneously. Chapter 5 focuses on the lipid transport Mla proteins. These proteins, MlaC, MlaD and MlaA were shown to be a favourable environment for lipid binding, where the docking of the protein components is explored in tandem with modelling. The focus of Chapter 6 is chaperone behaviour. LolA was shown to bind the BLP lipid moiety and that the MAC13243 molecule inhibited interaction, but not binding. Apolipoprotein-D showed preference for arachidonic acid and cholesterol, displaying a similar theme of small hydrophobic ligand binding as LolA. These studies have provided insight into molecular I nteractions that occur on a microscopic level within biological simulation.

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Identifiers

ORCID for Alister Boags: orcid.org/0000-0003-3072-3720

ORCID for Syma Khalid: orcid.org/0000-0002-3694-5044

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