Folding and design of beta sheets in membranes

描述(由申请人提供)：结构工程的最终目标之一 生物学是多肽和蛋白质的从头设计和合理工程 结构。在几个领域朝着这一目标取得了重大进展 然而，膜蛋白，特别是β-片膜蛋白， 只是很少被研究。膜β结构丰富，并具有 与许多重要的生物过程有牵连，但很少有 了解β-折叠原理和膜的结构。在……里面 在之前的研究中，我们发现了几个家族的短疏水多肽 在膜中协同折叠成寡聚的β-折叠，表明 膜的任何部分的β-折叠的形成主要是由 氢键相互作用。基于这个想法，我们假设有三个 多肽在脂类中形成β-折叠的必要条件 双层膜：1)多肽必须具有足够的疏水性以稳定地分配 进入膜；2)它必须能够形成具有疏水性的β-片层 膜相互作用的表面；以及3)它必须具有不利的序列 阿尔法-螺旋队形。特别是，我们假设一个跨膜的 β-桶只能由具有交替序列的多肽形成 疏水和亲水残基，或二重重复序列基序。这个 这里提出的研究旨在检验这一假设的各个部分 以几种互补的方式：通过迭代多肽设计，通过 基础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 这里提出的建议是为了更好地理解测试表的基本原理 在膜中折叠，并将该信息用于从头设计 使用多肽系统的跨膜贝塔桶。

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.