Folding and design of beta sheets in membranes

描述（由申请人提供）：结构化的最终目标之一 生物学是肽和蛋白质的重新设计和合理工程 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折叠膜蛋白， 很少被研究。膜β-结构丰富， 它与许多重要的生物过程有关，但很少被 了解β折叠的原理和膜的结构。在 在以前的研究中，我们发现了几个短疏水肽家族， 在膜中协同折叠成寡聚体β-折叠，这表明， 在膜的任何部分中的β-折叠形成主要通过强的 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）肽必须足够疏水以稳定分配 2）它必须能够形成具有疏水性的β-折叠; 膜相互作用表面;和3）它必须有一个序列，不利于 α-螺旋形成。特别是，我们假设一个跨膜的 β-桶只能由具有以下交替序列的肽形成： 疏水和亲水残基或二联体重复序列基序。的 这里提出的研究旨在验证这一假设的各个部分 在几个互补的方式：通过迭代肽设计，通过 基本的热力学测量，并通过基因组方法， 检测和结构预测。研究的长期目标 这里提出的是更好地理解β折叠的基本原理， 并利用这些信息重新设计 跨膜β-桶使用肽系统。

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.