Structural Transitions in Proteins and Protein Assemblies

蛋白质和蛋白质组装体的结构转变 项目摘要/摘要 详细了解蛋白质的化学组成和结构/功能之间的关系 对于理解疾病途径和药物在细胞水平上的作用至关重要。去- 尽管进行了几十年的实验和计算研究，但这种关系仍然只是部分 明白了。在本项目中，我们开发了先进的计算方法来研究 很难在实验中探索的结构性变化，但因为它们发生了变化，所以很重要 蛋白质的功能，或蛋白质聚集体的毒性。这些技术经过了测试，并获得了最佳效果。 在对两种蛋白质RfaH-CTD和淋巴动蛋白的研究中进行了合成，这两种蛋白质通过切换来改变它们的功能 在两个不同的结构之间。虽然专注于简单的模型系统，但获得的洞察力可能 指导治疗应用，例如，稳定特定Confor的组件的设计- 信息传递。在第二组模拟中，我们将我们的技术和概念扩展到齐聚 淀粉样蛋白形成A肽，与阿尔茨海默病有关。结合我们的计算能力 南密西西比大学兰加卡里实验室的实验研究， 我们将研究有毒和无毒(或毒性较小)聚集体之间的转换，以及为什么一些 淀粉样蛋白可以通过转换其他形式来为自己的生长提供种子。了解这一过程可能会在 转而导致药物的发展，以调节这种“传染性菌株”的传播。

Structural Transitions in Proteins and Protein Assemblies Project Summary/Abstract A detailed knowledge of the relation between chemical composition and structure/function of proteins is crucial for an understanding of disease pathways and the working of drugs at the level of cells. De- spite decades of research, both experimental and computational, this relationship is still only partially understood. In the present project, we develop advanced computational methodologies to investigate structural changes that are difficult to probe in experiments, but are important because they change the function of proteins, or the toxicity of protein aggregates. These techniques are tested and opti- mized in studies of two proteins, RfaH-CTD and lymphotactin, that change their function by switching between two different structures. While focusing on simple model systems, the gained insight may guide therapeutic applications, for instance, the design of components that stabilize a certain confor- mation. In a second set of simulations we extend our techniques and concepts to the oligomerization of amyloid-forming A -peptides, implicated in Alzheimer's disease. Combining our computational studies with experimental investigations by the Rangachari Lab at University of Southern Mississippi, we will study the transition between toxic and non-toxic (or less toxic) aggregates, and why some amyloids can seed their own growth by converting other forms. Understanding this process may in turn lead to the development of drugs that modulate the spread of such “infectious strains”.