Folding and design of beta sheets in membranes

膜中β片层的折叠和设计

• 批准号: 6520097
• 负责人: WILLIAM C WIMLEY
• 金额: $ 18.56万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520097
• 关键词: biotechnology; calorimetry; circular dichroism; combinatorial chemistry; computer simulation; fluorescent dye /probe; functional /structural genomics; high performance liquid chromatography; hydropathy; infrared spectrometry; lipid bilayer membrane; membrane model; membrane proteins; model design /development; peptide chemical synthesis; peptide library; peptide structure; protein engineering; protein folding; protein sequence; protein structure function; proteomics; structural biology; thermodynamics

Description (provided by applicant): One of the ultimate goals of structural biology is the de novo design and rational engineering of peptide and protein structure. Significant progress toward this goal has been made in several areas however the membrane proteins, particularly beta-sheet membrane proteins, have been studied only infrequently. Membrane beta-structures are abundant and have been implicated in a number of important biological processes and yet little is known about the principles of beta-sheet folding and structure in membranes. In previous studies we found several families of short hydrophobic peptides that fold cooperatively into oligomeric beta-sheets in membranes, suggesting that beta-sheet formation in any part of a membrane is stabilized mainly by strong hydrogen-bonding interactions. Based on this idea, we hypothesize that three conditions are necessary for a polypeptide to form beta-sheets in a lipid bilayer membrane: 1) the peptide must be hydrophobic enough to stably partition into the membrane; 2) it must be able to form a beta-sheet with hydrophobic membrane-interacting surfaces; and 3) It must have a sequence that disfavors alpha-helix formation. In particular, we hypothesize that a membrane-spanning beta-barrel can only be formed by a peptide with an alternating sequence of hydrophobic and hydrophilic residues, or dyad repeat sequence motif. The research proposed here is designed to test the various parts of this hypothesis in several complimentary ways: through iterative peptide design, through fundamental thermodynamic measurements and through genomic approaches to detection and structure prediction. The long term objectives of the studies proposed here are to better understand the fundamental principles of beta-sheet folding in membranes and to use that information for the de novo design of membrane-spanning beta-barrels using peptide systems.

描述（由申请人提供）：结构的最终目标之一 生物学是肽和蛋白质的从头设计和合理工程 结构。在实现这一目标的过程中，多个领域都取得了重大进展 然而，膜蛋白，特别是β-折叠膜蛋白，具有 只是很少被研究。膜β结构丰富且具有 与许多重要的生物过程有关，但很少有人知道 了解β-折叠的原理和膜的结构。在 之前的研究我们发现了几个短疏水肽家族 协同折叠成膜中的寡聚β-片层，表明 膜任何部分的 β-折叠形成主要通过强作用来稳定 氢键相互作用。基于这个想法，我们假设三个 多肽在脂质中形成β-折叠所必需的条件 双层膜：1）肽必须具有足够的疏水性才能稳定分配 进入膜； 2）它必须能够形成具有疏水性的β-折叠 膜相互作用表面； 3）它必须有一个不利于的序列 α螺旋的形成。特别是，我们假设跨膜 β-桶只能由具有交替序列的肽形成 疏水性和亲水性残基，或二元重复序列基序。这 这里提出的研究旨在检验该假设的各个部分 以几种互补的方式：通过迭代肽设计，通过 基本的热力学测量和通过基因组方法 检测和结构预测。研究的长期目标 这里提出是为了更好地理解 beta-sheet 的基本原理 折叠膜并将该信息用于从头设计 使用肽系统的跨膜β-桶。