In addition to being an energy source in biological reactions, recent discoveries suggest adenosine triphosphate (ATP) also plays a critical role in maintaining cell stability and preventing deleterious cellular processes through modulating biomacromolecular self assembly. ATP has been shown to inhibit aggregation of fibril forming proteins linked to diseased states, to direct the formation of membraneless organelles, and to inhibit association of eye proteins linked to age-related cataracts (Patel et al., 2017 Science 356: 753; Greiner et al., 2019 Exp Eye Res. 190:107862). In this work, we will elucidate the molecular basis for stabilizing effects of ATP through a combination of computational modelling and measurements of intermolecular interactions and protein aggregation behaviour. The findings will provide important insights for controlling diseased states in cells, but have broader implications for biological medicines. Small multivalent ions such as ATP could be used for increasing the colloidal stability of gene therapies and next generation biopharmaceuticals, which are increasingly difficult to manufacture due to physical instabilities. Research Training: The project provides training in a broad range of biophysical characterization methods combined with molecular modelling and informatics approaches for elucidating intermolecular interactions. The Curtis lab contains a suite of light scattering detectors, an electrophoretic light scattering detector, and a size-exclusion chromatography-multi angle laser light scattering (SEC-MALLS) set-up, all of which will be used off-line for protein physical stability indicators. Some of the work will use the analytical facilities at Manchester including temperature programmable multi-detection systems for high throughput stability screening and analytical ultracentrifugation. The Warwicker lab will oversee the modelling studies and runs an on-line solubility prediction website for proteins which will be used and developed as part of the work. The project will be part of a larger grouping of academics and students focused on research into the next generation of bioprocessing and formulation development. As part of this grouping, the student will have access to academic and industrial workshops focusing on all aspects of biopharmaceutical development including cell biosciences, downstream bioprocessing, formulation development and bioanalytical characterization. These will showcase how tools developed in academia are now being applied in an industrial environment.
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