UNDERSTANDING B-SHEET STRUCTURE IN AQUEOUS SOLUTION

了解水溶液中的 B 片结构

• 批准号: 2189401
• 负责人: JEFFERY W KELLY
• 金额: $ 12.45万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2189401
• 关键词: benzofurans; chemical stability; circular dichroism; computer simulation; conformation; crystallization; cyclic peptides; fluorescence spectrometry; hydrogen bond; hydropathy; intermolecular interaction; ionic bond; nuclear magnetic resonance spectroscopy; peptide chemical synthesis; protein denaturation; protein folding; protein sequence; protein structure; structural biology; thermodynamics; ultracentrifugation; water solution

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.

这项研究的长期目标是了解这种化学物质 控制折叠、稳定性和自结合的原理 多肽和蛋白质中的β-折叠。Beta-Sheet指的是第二个 两个或多个延伸的多肽链与一个相互作用的结构 另一种是通过氢键和疏水相互作用产生 片状折叠。小而清晰的Beta-Sheet的制备 事实证明是非常困难的，因为他们倾向于接受自我 与分子内竞争或排除分子内的结合 折叠。二苯并呋喃类氨基酸残基的开发， 它引导其邻近的α-氨基酸残基折叠成一个 反平行Beta-Sheet结构，代表了一种可靠的创建方式 在水溶液中具有明确的Beta-Sheet结构。异苯并呋喃 取代了通常的环状区域或贝塔转角区域，这是理想的 从它不会显著干扰 β-Sheet结构。事实证明，类似的方法对于创建 水溶液中的小平行Beta-Sheet。 这项提案的重点是了解二苯并呋喃基氨基 酸能够控制α-氨基酸序列的折叠， 它被并入了。低分辨率和高分辨率光谱 将使用方法来表征所产生的Beta-Sheet和 研究与快速折叠有关的构象。 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 静电相互作用使稳定化或 破坏Beta-Sheet二级结构的稳定性。这些床单也将 用于启动长期研究，以了解Beta-Sheet中介 自我组装。目标是探索分子需求 用于分子间片层的形成，并学习如何防止不受欢迎的 片状促进将正常溶解的蛋白质自组装成 不可溶的第四代Beta-Sheet结构，称为淀粉样原纤维， 被认为是阿尔茨海默氏症和相关疾病的致病因素。 这里描述的工作的意义在于，它是一种努力 开始了解Beta-Sheet的物理属性。