Photo-initiated Disassembly of Fibrils: Application to Amyloids and Hydrogels

描述(申请人提供)：蛋白质自组装，即单体自发地组织成高度有序的结构，已成为生物学研究的一个重要方面。有很大一部分致力于了解错误折叠的蛋白质导致的不溶性淀粉样蛋白沉积的自组装，这与阿尔茨海默氏症、帕金森氏症和II型糖尿病等不治之症有关。与此同时，蛋白质/多肽自组装的研究也活跃在生物结构和支架的设计中，如多肽水凝胶，这些生物结构和支架具有许多新的应用，从再生医学到治疗药物的输送。更有趣的是，这种蛋白质/肽组件，例如淀粉样蛋白和水凝胶，在结构上有相似之处，例如通过交叉β-Sheet排列形成高度有序的纤维。研究表明，自组装受疏水侧链相互作用的调节，导致不同的疏水核心或簇的组装，从而稳定β-Sheet排列。这一建议是基于这样一种想法，即通过在纤维内部引入一种能够产生光的部分 通过激活电荷，我们可以显著削弱对聚集体、纤维或水凝胶基质组装至关重要的疏水相互作用，并潜在地破坏这些明确定义的结构。这项提议将通过使用一种不耐光的赖氨酸类似物二甲氧基-2-硝基苯甲氧羰基(Lys(Nvoc))来测试这一前提，该类似物是疏水的，但在光裂解时会产生带电的赖氨酸，以光触发淀粉样蛋白和其他形成纤维的多肽水凝胶的解离。由于光笼的芳香性，引入Lys(Nvoc)取代其他疏水残基有望在照射前保持聚集倾向，而光裂解将在这些位置产生电荷，诱导纤维解离。这些实验的结果将提供一种新的方法来操纵原本不可逆的结构的构象，可能在淀粉样蛋白相关的治疗研究和/或功能生物材料的合理设计中提供创新和新颖的生物学应用。

DESCRIPTION (provided by applicant): Protein self-assembly, the spontaneous organization of monomers into highly ordered structures, has become a significant aspect of biological research. A large portion is dedicated to understanding the self-assembly of insoluble amyloid deposits from misfolded proteins, which has been linked to incurable diseases, such as Alzheimer's, Parkinson's, and Type II Diabetes. At the same time, the investigation of protein/peptide self-assembly is also active in the design of biological architectures and scaffolds, such as peptide hydrogels, that have many new applications, ranging from regenerative medicine to the delivery of therapeutics. What is more interesting is that such protein/peptide assemblies, e.g. amyloids and hydrogels, share structural similarities, such as formation of highly ordered fibrils with cross β-sheet arrangements. Studies have shown that self-assembly is regulated by hydrophobic side chain interactions causing the assembly of a distinct hydrophobic core or cluster, which stabilize β-sheet arrangements. This proposal is founded on the idea that by introducing into the fibril interior a moiety which can produce a light activated charge, we can significantly weaken the hydrophobic interactions crucial to the assembly of aggregates, fibrils, or hydrogel matrices, and potentially disrupt these well-defined structures. This proposal will test this premise by using a photolabile lysine analog, dimethoxy-2-nitrobenzyloxycarbonyl (Lys(nvoc)), which is hydrophobic but yields a charged lysine upon photocleavage, to photo-trigger the dissociation of amyloids and other fibril forming peptide hydrogels. Introducing Lys(nvoc) in the place of other hydrophobic residues is expected to conserve the aggregation propensity prior to irradiation due to the aromatic nature of the photocage, while photocleavage will produce a charge at these positions to induce disassembly of fibrils. The results of these experiments will provide a novel way to manipulate the conformations of otherwise irreversible structures, potentially providing innovative and novel biological applications within amyloid related therapeutic research and/or the rational design of functional bionanomaterials.