Biophysical dissection of protein nucleation using a combined experimental and computational approach

蛋白质负责生物体的绝大多数功能，在那里它们制造结构支架，将货物从A运送到B，在细胞之间传递信息，识别和击退入侵者，并催化生命所必需的反应。蛋白质自我组装成明确的结构和许多分子的结构对我们的健康也是必不可少的。然而，有时蛋白质的自我组装会不适当地发生，可能是由于突变或环境的变化。当这种情况发生在体内时，通常会导致疾病，而肺气肿、阿尔茨海默病、帕金森氏症、白内障和II型糖尿病等疾病都被认为是蛋白质自我组装不当的结果。蛋白质自组装也会在工业过程中造成严重破坏，包括胰岛素等生物制药的生产。当这种情况发生时，药物通常会以不可挽回的胶状蛋白质团块的形式丢失。然而，并没有失去一切：蛋白质的自我组装也支撑了包括鸡蛋、肉类和奶制品在内的食品的质地。我们感兴趣的是一种特殊的蛋白质自组装形式，这种形式似乎对所有蛋白质都是共同的。一种特殊的自组装形式似乎适用于化学上非常不同的广泛物种(蛋白质从数百个原子到数十万个原子)，这可能与直觉相反，然而这种形式的自组装是由蛋白质链主干上的基团驱动的，而这个主干是所有蛋白质共同的聚合物。在这种情况下，自我组装的结果是形成“淀粉样”纤维，即由数千个相同蛋白质拷贝组成的绳状结构。我们感兴趣的是开始组装这些纤维的最早阶段。如果所有的蛋白质都可以进行这种形式的自组装，如果所有的蛋白质形成相同的最终纤维结构，它们是否也遵循相同的途径？我们建议使用化学、生物物理和物理领域的一系列非常不同的互补技术，以及最先进的实验和计算方法的组合来检测、识别和表征自组装中最早的物种。

Proteins are responsible for the vast majority of functions in living organisms, where they make structural scaffolds, transport cargo from A to B, pass messages from cell to cell, recognise and repel invaders, and catalyse the reactions essential for life. The self-assembly of proteins into well-defined structures and into constructs of many molecules is also essential to our well-being. Occasionally, however, protein self-assembly takes place inappropriately, perhaps due to a mutation or a change in environment. When this happens in the body it typically causes disease, and diseases such as emphysema, Alzheimer's Disease, Parkinson's Disease, cataract and type II diabetes are all recognised to be the result of improper protein self-assembly. Protein self-assembly can also cause havoc in industrial processes including the production of biopharmaceuticals such as insulin. When this occurs, the pharmaceutical is often lost as an irretrievably tangled mass of gelled protein. All is not lost, however: the self-assembly of proteins also underpins the texture of foodstuffs including egg, meat and milk products. We are interested on one specific form of protein self-assembly that appears to be common to all proteins. It is possibly counter intuitive that a specific form of self-assembly seems to apply to a wide range of chemically very different species (proteins range from hundreds of atoms to hundreds of thousands of atoms), however this form of self-assembly is driven by groups in the backbone of the protein chain, and this backbone is a polymer common to all proteins. The outcome of self-assembly in this case is the formation of 'amyloid' fibrils, rope-like structures consisting of thousands of copies of the same protein. We are interested in the earliest stages that start the assembly of these fibrils. If all proteins can undergo this form of self-assembly, and if all proteins form the same final fibrillar structure, do they all also follow the same pathway? We propose to use a range of very different complementary techniques from the fields of chemistry, biophysics and physics, and a combination of state-of-the-art experimental and computational approaches to detect, identify and characterise the earliest species in self-assembly.