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

描述（由申请人提供）：蛋白质自组装，单体自发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。很大一部分致力于了解错误折叠蛋白质的不溶性淀粉样蛋白沉积物的自组装，这与无法治愈的疾病有关，如阿尔茨海默氏症，帕金森氏症和II型糖尿病。同时，蛋白质/肽自组装的研究也活跃在生物结构和支架的设计中，例如肽水凝胶，其具有许多新的应用，从再生医学到治疗剂的递送。更有趣的是，这样的蛋白质/肽组装体，例如淀粉样蛋白和水凝胶，具有结构相似性，例如形成具有交叉β-折叠排列的高度有序的原纤维。研究表明，自组装是由疏水侧链相互作用调节的，引起不同疏水核心或簇的组装，其稳定β-折叠排列。这个建议是基于这样的想法，即通过在原纤维内部引入一个可以产生光的部分， 通过激活电荷，我们可以显著削弱对聚集体、原纤维或水凝胶基质的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。该提案将通过使用光不稳定的赖氨酸类似物，二甲氧基-2-硝基苄氧基羰基（Lys（nitrobenzyoxycarbonyl，Lys（nitrobenzyoxycarbonyl）），其是疏水性的，但在光裂解时产生带电赖氨酸，以光引发淀粉样蛋白和其他原纤维形成肽水凝胶的解离来测试这一前提。由于光笼的芳香族性质，预期引入Lys（nucleotide）代替其他疏水残基在照射之前保持聚集倾向，而光裂解将在这些位置产生电荷以诱导原纤维的分解。这些实验的结果将提供一种新的方法来操纵构象，否则不可逆的结构，潜在地提供创新和新颖的生物学应用内淀粉样蛋白相关的治疗研究和/或功能性生物纳米材料的合理设计。

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.