Peptide-induced reorganization of lipid assemblies

肽诱导的脂质组装重组

• 批准号: RGPIN-2019-04962
• 负责人: Morrow, Michael
• 金额: $ 2.04万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=737977
• 关键词: Peptide; induced; reorganization; lipid; assemblies

Lipid molecules have water-soluble heads and oily tails. They assemble into bilayers, as in cell membranes, multilayers, as in lung surfactant, and micelles. Many biological processes involve reorganization of lipid assemblies by proteins or polypeptides with specific structures and charge distributions. For example, special proteins enable formation of a lipid layer, at the lung air-water interface, that permits lung inflation and thus breathing. Other polypeptides help organisms resist bacterial infection. We will study how lipid-peptide interactions promote lipid assembly reorganization in: (1) the spreading of surfactant layers at the air-water interface in lungs and (2) disruption of bacterial membranes by antimicrobial peptides (AMPs). We will also study (3) non-equilibrium behaviour in systems of "active" lipid particles. We will use nuclear magnetic resonance (NMR), light scattering, and calorimetry to study peptide-induced changes in the structures and motions of lipid assemblies and intact bacterial membranes. Solid state NMR has shown that some lung surfactant proteins promote interdigitation, the intermingling of lipid chains from opposing monolayers across the bilayer mid-plane to give thin, ordered layers. Interdigitation might thus be an important step in the transfer of surfactant material between the air-water interface and multilayer reservoirs. Object (1) is to learn how specific protein structural elements contribute to surfactant spreading by building temperature-composition phase diagrams for model lipid systems containing protein fragments selected for their capacity to promote surfactant reorganization including interdigitation. Object (1) has implications for the development of new treatments for serious respiratory conditions resulting from surfactant deficiency. In collaboration with V. Booth (Biochemistry), we successfully added deuterium to bacterial membranes and used 2H NMR to study membrane perturbation by AMPs and the effects of thinning the rigid outer walls of some bacteria. Object (2a) will be to study how perturbing the outer lipopolysaccharide layer present in other bacteria alters AMP effects on their inner and outer membranes. Object (2b) will be to learn how cardiolipin (CL), a bacterial and mitochondrial membrane lipid with four acyl chains and a pH-dependent charge, affects physical properties of membranes in which it is abundant. 2H NMR will be used to construct phase diagrams and study lipid motions in selected CL-containing model membranes. Object (2) has implications for the development of new strategies to control antibiotic-resistant bacteria. In collaboration with A. Yethiraj, object (3) will be to embed bacteriorhodopsin, a photoactivated proton pump, into nanoscale lipid bicelles which will be used to study non-equilibrium motion of active particles. This program aims to relate soft matter interactions to biological function and contribute insights with potential therapeutic relevance.

脂类分子有水溶性的头部和油性的尾部。它们聚集成双层，如细胞膜，多层，如肺表面活性物质，和胶束。许多生物过程涉及具有特定结构和电荷分布的蛋白质或多肽对脂类组装的重组。例如，特殊的蛋白质可以在肺的空气-水界面形成一层脂层，从而允许肺充气和呼吸。其他多肽可以帮助生物体抵抗细菌感染。我们将研究脂肽相互作用如何促进脂类组装重组：(1)肺内空气-水界面表面活性物层的铺展和(2)抗菌肽(AMPs)对细菌膜的破坏。我们还将研究(3)“活性”脂质粒子系统中的非平衡行为。我们将使用核磁共振(核磁共振)、光散射和量热法来研究多肽诱导的脂类集合体和完整细菌膜的结构和运动的变化。固体核磁共振显示，一些肺表面活性物质蛋白质促进交错，即来自相反的单层的脂链在双层中间平面混合，得到薄的、有序的层。因此，交错可能是表面活性物质在空气-水界面和多层储集层之间转移的一个重要步骤。目的(1)是通过为含有蛋白质片段的模型脂类体系建立温度-组成相图，了解特定的蛋白质结构元素如何促进表面活性物质的扩散，包括交错指状作用。目的(1)对表面活性物质缺乏引起的严重呼吸系统疾病的新治疗方法的开发具有重要意义。在与V.Booth(生物化学)的合作下，我们成功地在细菌膜上添加了氘，并使用2H核磁共振研究了AMPS对膜的扰动以及减薄一些细菌坚硬的外壁的影响。目标(2a)将研究其他细菌中存在的外层脂多糖层如何改变AMP对其内膜和外膜的影响。目标(2b)将了解心磷脂(CL)，一种具有四个酰基链和一个pH依赖电荷的细菌和线粒体膜脂，如何影响其丰富的膜的物理性质。2H核磁共振将被用于构建相图和研究选定的含CL的模型膜中的脂质运动。目的(2)对开发控制抗生素耐药细菌的新策略具有重要意义。在与A.Yethiraj的合作中，目标(3)将把细菌视紫红质--一种光激活的质子泵--嵌入到纳米级的脂联体中，这将用于研究活性粒子的非平衡运动。该计划旨在将软物质相互作用与生物功能联系起来，并提供具有潜在治疗意义的见解。