UNDERSTANDING B-SHEET STRUCTURE IN AQUEOUS SOLUTION

这项研究的长期目标是了解化学物质 控制折叠、稳定性和自缔合的原理 肽和蛋白质中的β折叠。 β折叠是指 两条或多条延伸的多肽链与一条相互作用的结构 另一个通过氢键和疏水相互作用产生 片状褶皱。 小的明确的β-折叠的制备具有 这是一个非常困难的，因为他们倾向于经历自我， 与分子内结合竞争或排斥 折页. 二苯并呋喃基氨基酸残基的开发， 其引导其相邻的α-氨基酸残基折叠成 反平行β折叠结构，代表了一种可靠的方法， 在水溶液中形成明确的β折叠结构。 异苯并呋喃 取代了通常的环路或β转弯区域， 从它不会显著干扰 β-折叠结构。 类似的方法已被证明有助于创建 水溶液中的小平行β-片层。 该提案的重点是了解二苯并呋喃基氨基 氨基酸能够控制α-氨基酸序列的折叠， 它被并入。 低分辨率和高分辨率光谱 方法将用于表征所得β-片层， 来研究被认为是导致快速折叠的构象。 协同折叠的β折叠结构将在尿素中变性 以确定疏水效应或 静电相互作用使其趋于稳定， 使β折叠二级结构不稳定。 这些床单还将 用于启动长期研究，以了解β折叠介导的 自我组装 目的是探索分子要求 分子间片层的形成，并学习如何防止不必要的 通常可溶性蛋白质的片状促进自组装成 不溶性四级β-折叠结构，称为淀粉样蛋白原纤维， 被认为是阿尔茨海默氏症和相关疾病的致病因子。 这里所描述的工作的意义在于，它是一种努力， 开始了解β-折叠的物理性质。

The long term goal of this research is to understand the chemical principles controlling the folding, stability and self-association of Beta-sheets in peptides and proteins. A Beta-sheet refers to a secondary structure where two or more extended polypeptide chains interact with one another via hydrogen bonding and hydrophobic interactions to create a sheet-like fold. The preparation of small well-defined Beta-sheets has proven to be a very difficult because of their tendency to undergo self- association in competition with, or to the exclusion of, intramolecular folding. The development of a dibenzofuran-based amino acid residue, which directs its neighboring alpha-amino acid residues to fold into an antiparallel Beta-sheet structure, represents a reliable way to create a well-defined Beta-sheet structure in aqueous solution. The ibenzofuran replaces what would normally be a loop or a Beta-turn region and is ideal from the perspective that it does not significantly interfere with the beta-sheet structure. A similar approach has proven useful for creating small parallel Beta-sheets in aqueous solution. This proposal focuses on understanding how the dibenzofuran-based amino acid is able to control the folding of an alpha-amino acid sequence that it is incorporated into. Both low and high resolution spectroscopic methods will be employed to characterize the resulting Beta-sheets and to study the conformation thought to be responsible for rapid folding. Beta-sheet structures that fold cooperatively will be denatured in urea to determine the contributions that the hydrophobic effect or electrostatic interactions make towards either stabilizing or destabilizing the Beta-sheet secondary structure. These sheets will also be used to initiate long term studies to understand Beta-sheet mediated self-assembly. The objectives are to explore the molecular requirements for intermolecular sheet formation and learn how to prevent undesirable sheet-facilitated self-assembly of normally soluble proteins into an insoluble quaternary Beta-sheet structure, known as an amyloid fibril, is thought to be the causative agent in Alzheimer's and related disease. The significance of the work described here is that it is an effort to begin to understand the physical properties of Beta-sheets.