Why do proteins aggregate under flow?

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The function and stability of proteins are intimately linked to their environment and consequently, changes in environmental factors such as pH can trigger conformational changes that in turn modulate protein function. Forces exerted onto proteins during fluid flow (i.e.hydrodynamic forces) are also used in Nature controlling processes such as blood clotting and spider silk formation but our understanding of this process is limited. To address this question, we have developed an instrument to that mimics these forces and used it to show that that fluid flow can drive the aggregation of a small test protein (BSA) by triggering unfolding, exposing new protein surfaces with greater self-affinity, leading to aggregation (see Dobson et al. (2017) Proc Natl Acad Sci USA. 114:4673-4678). In addition to in vivo processes, fluid-flow induced unfolding and aggregation presents a huge obstacle to the large-scale manufacture of protein-based therapeutics and sometimes even prevents the translation of a promising candidate therapeutic to an effective and safe medicine. Protein-based medicines, known as biopharmaceuticals have emerged as powerful and versatile medicines with applications in auto-immune disease and cancer with antibody-based therapies having sales of $123 billion in 2017. The goal of this BBSRC Collaborative Training Partnership PhD studentship between the Astbury Centre for Structural and Molecular Biology and Medimmune, therefore, is to apply Leeds' unique expertise in protein (un)folding mechanisms, biophysical characterisation and hydrodynamic flow to identify the mechanism of flow-induced unfolding of test proteins and biopharmaceuticals provided by Medimmune. This fundamental study will ultimately facilitate the economic production of current and next generation high-value bio-pharmaceuticals.