Total protein synthesis: a new tool for studies of the structure and stability of amyloid fibrils

淀粉样蛋白疾病包括许多众所周知的病症，例如阿尔茨海默病和新的变体克鲁茨-雅各布病。所有这些条件都涉及蛋白质分子聚集成大的不溶性纤维。这项研究的目的是了解蛋白质如何在分子水平上组装成淀粉样纤维。我们的目标是通过改变β-2-微球蛋白的结构来实现这一目标，β-2-微球蛋白是一种与淀粉样蛋白有关的蛋白质，影响所有长期肾透析的人，并研究蛋白质序列的变化如何改变蛋白质形成淀粉样蛋白原纤维的能力。在这项特殊的研究中，我们将改变蛋白质的基本骨架结构，这种操作无法使用生物化学方法进行。相反，我们将在实验室反应器中使用化学合成每个酰胺键来合成整个蛋白质结构。化学方法不像生物化学那样有局限性，因此我们可以对靶蛋白的基本结构进行深刻的改变。通过研究这些蛋白质结构的变化如何改变其形成淀粉样蛋白纤维的能力，我们将阐明有关淀粉样蛋白纤维的结构和稳定性的新信息，这些信息将为未来开发针对这些致命疾病的新疗法提供信息。

Amyloid diseases include many well known conditions such as Alzheimer's disease and new variant Cruetzfeld-Jakob disease. All these conditions involve the aggregation of protein molecules into large insoluble fibrils. The purpose of this research is to understand how proteins assemble into amyloid fibrils at the molecular level. We aim to achieve this by altering the structure of beta-2-microglobulin, a protein involved in an amyloid condition that affects all people on long-term renal dialysis, and to investigate how the changes to the protein sequence alter the ability of the protein to form amyloid fibrils. In this particular study we will make changes to the fundamental backbone structure of the protein and such manipulations can not be made using biochemical methods. Instead we will synthesise the whole protein structure using chemistry making each amide bond in a laboratory reactor. The chemical approach does not have the same limitations as biochemistry and so we can make profound changes to the fundamental structure of the target protein. By studying how these changes to the protein structure alter its ability to form amyloid fibres we will elucidate new information about the structure and stability of amyloid fibrils that will inform future work to develop new therapies against these fatal diseases.