Antibiotic resistance has always fascinated me, and I have always known that I wanted to make a contribution in this field. My biochemistry degree at the University of Leeds further cemented this belief, and I realised I also particularly enjoyed learning about protein folding, one of the most important processes that occurs to allow a cell to function. This PhD very much appealed to me as it combined my two interests into one project, allowing me to scrutinise how a particular set of proteins fold, with the end goal of informing drug design to combat antibiotic resistance.
Understanding how proteins fold to their functional 3D structures is one of the greatest unsolved mysteries in biology. While great strides have been made in understanding how water-soluble proteins fold, how membrane proteins fold remains poorly understood. One particularly fascinating class of proteins is the outer membrane proteins (OMPs) of gram negative bacteria. These proteins adopt complex beta-barrel structures that pack closely in the highly unusual asymmetric outer membrane (OM). Maintenance of the cell wall is vital for bacterial survival, hence a new understanding of how OMPs fold is not only of immense fundamental importance, but could stimulate new routes to combat antibiotic resistance in gram negative pathogens.
I will investigate the mechanism of OMP folding using transmembrane beta barrels, de novo designed proteins which do not have any evolutionary history, and therefore can be used as a ‘blank slate’ to interrogate how a protein sequence affects where the protein localises, and what interactions it makes along the way. Furthermore, these transmembrane beta barrels also have application in nanopore technology, and may be used for sequencing methods.