RUI: Investigations of a Novel, Bimetallic Ring System for Nucleating Beta-Sheets

有了这个奖项，化学系的化学结构，动力学机制B计划正在资助Trinity学院化学系的Timothy Curran教授开发用于探索β-折叠的物理和化学性质的模型系统，β-折叠是一种常见的蛋白质二级结构，其中两条蛋白质链彼此平行排列。 β-折叠的形成与淀粉样蛋白疾病如阿尔茨海默病有关。 虽然有现有的β-折叠模型系统，但它们的使用受到限制，因为这些模型系统聚集并变得不可溶，使它们难以研究。 Curran教授和他的学生发现了一种刚性的环状分子，它包含了金属，铁和钨，他们还发现了将两条短蛋白质链附加到这个环状分子上的方法。 这些蛋白质链彼此平行排列。 这项研究的目的是确定连接到刚性环状分子的两条蛋白质链是否会形成β-折叠，以及铁和钨原子的变化是否可以防止聚集问题。 如果成功，这项工作将使其他研究人员能够更好地了解驱动β-折叠形成的力量。 该项目位于有机，无机和生物化学的界面，因此非常适合本科理科学生的教育。 本科生同事，包括那些来自科学界代表性不足的团体，以及一些高中生将参加这个资助项目。钨双（炔）配合物是ununsual，因为它们是空气稳定的。一般来说，炔配体围绕钨中心旋转;这对于无环和环状络合物都是如此。在最近的工作中，一个环状钨双（炔）配合物衍生自二炔基1，1 '-二取代二茂铁已被发现，并发现在溶液中，而刚性并列的两个炔配体。 该环系统的刚性性质及其保持两个炔的能力将被用于探索附加到两个炔的肽是否会产生跨链氢键并采用β-折叠构象。 肽将通过与亚甲基胺或亚甲基羧基接头形成的酰胺键连接到炔上。 如果这些肽衍生物确实采用β-折叠构象，则将评估其聚集能力。 如果观察到聚集，则将检查二茂铁部分中的铁原子的氧化，以确定电荷-电荷排斥是否可以破坏聚集。 这项工作的长期目标是开发一个模型系统，用于研究β-折叠和有助于其聚集的因素。

With this award, the Chemical Structure, Dynamics & Mechanisms B Program of the Division of Chemistry is fudning Professor Timothy Curran of the Department of Chemistry at Trinity College to develop model systems for exploring the physical and chemical properties of beta-sheets, a common protein secondary structure wherein two protein chains are aligned parallel to each other. Formation of beta-sheets has been implicated in amyloid diseases such as Alzheimer's disease. Although there are existing model systems for beta-sheets, their use has been limited because these model systems aggregate and become insoluble, making them difficult to study. Professor Curran and his students have discovered a rigid, cyclic molecule that incorporates the metals, iron and tungsten, and they have discovered ways to append two short protein chains to this cyclic molecule. These protein chains are aligned parallel to each other. The goal of this research is to determine whether the two protein chains linked to the rigid cyclic molecule will form beta-sheets, and whether changes to the iron and tungsten atoms can prevent the problem of aggregation. If successful this work will enable other researchers to better understand the forces that drive beta-sheet formation. The project lies at the interface of organic, inorganic and biochemistry, and is therefore well suited to the education of undergraduate science students. Undergraduate co-workers, including those from groups underrepresented in sciences, and some high school students will take part in this funded project.Tungsten bis(alkyne)complexes are ununsual in that they are air stable. In general, the alkyne ligands rotate around the tungsten center; this is true for both acyclic and cyclic complexes. In recent work, a cyclic tungsten bis(alkyne) complex derived from a dialkynyl 1,1'-disubstitutedferrocene has been discovered and found to rather rigidly juxtapose the two alkyne ligands in solution. The rigid nature of this ring system and its ability to hold the two alkynes in close proximity will be used to explore whether peptides appended to the two alkynes will develop cross-strand hydrogen bonds and adopt beta-sheet conformations. Peptides will be appended to the alkynes via amide bonds made to either methyleneamine or methylenecarboxyl linkers. If these peptide derivatives do adopt beta-sheet conformations, then their ability to aggregate will be assessed. If aggregation is observed, oxidation of the iron atom in the ferrocene moiety will be examined to determine whether charge-charge repulsion can disrupt aggregation. The long-term goal of this work is to develop a model system for studying beta-sheets and the factors that contribute to their aggregation.