PhD project: Physics of the bacterial genome

Project description

For many years it was thought that bacteria were largely unstructured "bags" of enzymes and DNA. More recently, is has been discovered that the bacterial genome is actually highly structured. In most bacteria the genome consists of a large circular chromosome and several smaller circular DNA molecules called plasmids. The chromosome, along with a set of associated proteins, forms the bacterial 'nucleoid'. As a bacterium grows and its DNA is replicated, the nucleoid and the plasmids have to be moved to different locations within the cell in a coordinated way. There are several different physical mechanisms involved in these 'positioning' processes, and we are interested in using computer simulations and methods from soft matter and statistical physics to better understand them.

Possible projects include:

1. Developing a model for antibiotic resistance plasmid segregation. As a bacterium grows it replicates its genome, and then divides into two daughter cells. Before division, the genome must be segregated into the two halves of cell. Some plasmids can be present in small numbers; for example there can be as few as two copies of a given plasmid prior to cell division. It is therefore crucial that the copies are correctly segregated, with one in each half of the cell before division, otherwise genetic information can be lost within a few generations. The genes which enable bacteria to be resistant to antibiotics often reside on such plasmids. It is therefore desirable to understand how plasmid segregation works, and how it might be interfered with to treat antibiotic resistant infections. The positioning mechanisms involved are thought to rely on non-equilibrium chemical reactions which set up protein gradients, and lead to a force being exerted on the plasmid. You will build on simple theoretical models and use coarse grained simulations to study these positioning processes. There will be opportunities to work with with experimental data from collaborators

2. Using simulations to understand how DNA supercoiling and protein binding shapes the nucleoid. When DNA is replicated or transcribed it becomes twisted, and writhes up - a phenomena known as supercoiling. Supercoiling changes the structure of the nucleoid, but also has an effect on transcription, meaning there can be interesting feedback effects. There are also many proteins which bind to DNA in a supercoiling dependent way. You will use coarse grained molecular dynamics simulations of DNA to study how supercoiling affects the structure of the nucleoid, and how this physical process is affected by protein binding and processes such as transcription. 

Some relevant references:

1.  Vincenzo G Benza et al., "Physical descriptions of the bacterial nucleoid at large scales, and their biological implications" Reports on Progress in Physics 75 076602 (2012)

2. J.-C. Walter et al., "Surfing on Protein Waves: Proteophoresis as a Mechanism for Bacterial Genome Partitioning" Physical Review Letters 119 028101 (2017)

3. Murray, S., Sourjik, V. "Self-organization and positioning of bacterial protein clusters" Nature Physics 13 1006-1013 (2017)

4. M. C. F. Pereira et al., "Entropic elasticity and dynamics of the bacterial chromosome: A simulation study" Journal of Chemical Physics 147 044908 (2017)

5. Yair A. G. Fosado, et al., "Nonequilibrium dynamics and action at a distance in transcriptionally driven DNA supercoiling" PNAS 118 e1905215118 (2021)  

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