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

蛋白质负责生物体中的绝大多数功能，在那里它们制造结构支架，将货物从A运输到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定义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，偶尔，蛋白质自组装发生不适当的，可能是由于突变或环境的变化。当这种情况发生在体内时，它通常会引起疾病，而诸如肺气肿、阿尔茨海默病、帕金森病、白内障和II型糖尿病等疾病都被认为是蛋白质自组装不当的结果。蛋白质自组装也会对工业过程造成破坏，包括胰岛素等生物药物的生产。当这种情况发生时，药物通常作为不可挽回地缠结的凝胶蛋白质团而丢失。然而，一切都没有失去：蛋白质的自我组装也是食品（包括鸡蛋、肉类和奶制品）质地的基础。我们感兴趣的是一种特殊形式的蛋白质自组装，似乎是共同的所有蛋白质。这可能是违反直觉的，一种特定形式的自组装似乎适用于广泛的化学上非常不同的物种（蛋白质范围从数百个原子到数十万个原子），然而这种形式的自组装是由蛋白质链主链中的基团驱动的，并且这个主链是所有蛋白质共同的聚合物。在这种情况下，自组装的结果是形成“淀粉样”纤维，即由数千个相同蛋白质拷贝组成的绳状结构。我们感兴趣的是这些纤维开始组装的最早阶段。如果所有的蛋白质都能经历这种形式的自组装，如果所有的蛋白质都形成了相同的最终纤维结构，那么它们是否也都遵循相同的途径？我们建议使用一系列来自化学，生物物理学和物理学领域的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，识别和识别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.