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

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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.