Why do proteins aggregate under flow?

蛋白质的功能和稳定性与其环境密切相关，因此，环境因素（如pH）的变化可引发构象变化，进而调节蛋白质功能。在流体流动过程中施加在蛋白质上的力（即流体动力）也用于自然控制过程，如血液凝固和蜘蛛丝形成，但我们对这一过程的理解是有限的。为了解决这个问题，我们开发了一种模拟这些力的仪器，并用它来表明流体流动可以通过触发解折叠、暴露具有更大自亲和力的新蛋白质表面来驱动小测试蛋白质（BSA）的聚集，从而导致聚集（见）多布森等人。（2017）美国国家科学院刊。114：4673-4678）。除了体内过程之外，流体流动诱导的解折叠和聚集对基于蛋白质的治疗剂的大规模制造提出了巨大的障碍，并且有时甚至阻止有希望的候选治疗剂转化为有效且安全的药物。基于蛋白质的药物，即生物制药，已成为功能强大、用途广泛的药物，应用于自身免疫疾病和癌症，2017年基于抗体的疗法的销售额为1230亿美元。因此，阿斯特伯里结构和分子生物学中心与Medimmune之间的BBSRC合作培训合作伙伴关系博士生项目的目标是应用利兹在蛋白质（非）折叠机制，生物物理表征和流体动力学流动方面的独特专业知识，以确定Medimmune提供的测试蛋白质和生物药物的流动诱导展开机制。这项基础研究将最终促进当前和下一代高价值生物制药的经济生产。

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.