The mechanism for amyloid formation in a model peptide

蛋白质是由20种不同的氨基酸组成的链，在细胞中合成后必须折叠成具有生物活性的形式。功能蛋白质在所有生物体中起着重要的结构和催化作用。然而，当蛋白质错误折叠时，它们可以形成明确的聚集体，一般称为淀粉样蛋白，并且现在已知在适当的条件下可以诱导多种蛋白质形成淀粉样蛋白。淀粉样蛋白的形成与许多严重的疾病有关，如阿尔茨海默氏病（老年性痴呆）、牛海绵状脑病（疯牛病）和克雅氏病（疯牛病的人类形式）。它还与饮食选择不当引起的糖尿病状况以及遗传特征有关，例如早发性痴呆。在合适的条件下，大范围的蛋白质可以发生聚集的认识是相对较新的，许多关于淀粉样蛋白形成的基本问题仍然没有解决。虽然普遍认为聚集是由从天然结构到一般片状结构（与丝中的结构相关）的构象变化引起的，但对该过程的机制细节知之甚少，并且发现其如何发生是淀粉样蛋白疾病治疗发展的关键优先事项。构象变化似乎是自传播的，因为速率随着反应的进行而增加。本项目的目标是阐明最近设计的人工蛋白质的结构从紧凑状态转变为淀粉样蛋白的机制。我们的目标是解决这个机制，在原子层次的细节，使用新开发的理论和计算机模拟技术。这些结果将为淀粉样蛋白的形成提供重要的新见解。特别是，可能会出现更具体和更精确的方法来预防和逆转淀粉样蛋白的形成，这对治疗人类疾病具有重要意义，包括衰老和与肥胖和饮食选择不当有关的疾病。

Proteins are chains constructed from twenty different amino acids, which must fold up into a biologically active form after they are synthesised in cells. The functional proteins play essential structural and catalytic roles in all living organisms. However, when proteins misfold they can form well-defined aggregates, generically known as amyloid, and it is now known that a wide variety of proteins can be induced to form amyloid under appropriate conditions. Amyloid formation has been implicated in a number of serious diseases, such as Alzheimer's (senile dementia), bovine spongiform encephalopathy (mad cow disease), and Creutzfeld-Jacob disease (the human form of mad cow disease). It is also associated with diabetic conditions caused by poorly chosen diets, as well as inherited traits, such as early onset forms of dementia. The realisation that aggregation can occur for a wide range of proteins under suitable conditions is relatively recent, and many fundamental questions concerning amyloid formation are still unresolved. Although there is general agreement that aggregation is induced by a conformational change from the native structure to a generic sheet-like structure (related to that in silk), little is known about the mechanistic details of this process, and discovering how it occurs is a key priority for the development of treatment for amyloid diseases. The conformational change appears to be self-propagating, since the rate increases as the reaction progresses. The goal of this project is to elucidate the mechanism by which the structure changes from a compact state into amyloid for a recently designed artificial protein. We aim to resolve this mechanism at an atomic level of detail using newly developed theory and computer simulation techniques. The results will provide important new insights into amyloid formation. In particular, more specific and precise methods to prevent and perhaps reverse amyloid formation may emerge, with important implications for the treatment of human disease, including aspects of ageing and conditions related to obesity and poorly chosen diets.