Sculpting Dynamic Amphiphilic Structures

雕刻动态两亲结构

• 批准号: EP/J017566/1
• 负责人: John Seddon
• 金额: $ 614.38万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FJ017566%2F1
• 关键词: Sculpting; Dynamic; Amphiphilic; Structures

Biomembranes lie at the heart of most biological function, and lipid membranes are increasingly finding a wide range of novel applications in biotechnology and nanomedicine. Such self-assembled amphiphilic interfaces can adopt an astonishing range of complex shapes and liquid-crystalline structures ordered in 1, 2 or 3 dimensions, over length scales stretching from 2 - 3 nanometres, to microns. Gaining an understanding at a molecular level of how interface structure, ordering, dynamics and micromechanics depend upon chemical structure and composition, and thermodynamic variables such as temperature, hydration, and pressure, is the key to learning how we can manipulate such self-assembled soft interfaces to create novel and useful structures and new technologies, and this is the main aim of this Programme. We have identified three key underpinning basic science challenges: 1) asymmetry; 2) patterning; 3) curvature, long-range organisation and symmetry. There are four main aspects underlying these challenges which we consider are of crucial importance: i) compositional asymmetry and dynamics of amphiphile flip-flop across bilayers; ii) lateral segregation, line tension and microdomain formation; iii) membrane curvature and curvature elasticity; iv) charge and dipolar interactions between lipid headgroups. Furthermore, there is a complicated coupling between all of these four aspects, and this is where we will focus much of our attention.We have assembled a team of five leading UK University research groups, spanning Chemistry, Physics and Biophysics. The groups have complementary expertise covering laboratory-based and synchrotron time-resolved X-ray diffraction, neutron scattering, solid-state nuclear magnetic resonance, calorimetry, biomolecular force microscopy, Langmuir trough and microfluidics technologies, linear and non-linear spectroscopies, atomic force microscopy, spectroscopic and optical imaging, optical tweezers, microrheology, and theory. These approaches will be used to attack different inter-related aspects of the three key basic science challenges. We will ensure an efficient translation and synthesis of all of the findings, by a tightly- regulated management structure, and by regular meetings and staff exchanges between the five research groups.Building on the engineering rules and technologies developed previously in the programme, we will integrate the earlier work to develop lipid structures into active lipid systems such as: self-encapsulated droplet interface bilayer networks in water; patterned asymmetric vesicles of defined size: coupling microfluidics with smart droplet microtools; phospholipid phases and vesicles in thermal gradients.We will then use this knowledge to develop three demonstration systems:i) Artificial Organelles. The development of artificial organelle machines which mimic some of the remarkable functions and properties of biology will lead to new approaches for personalized healthcare. ii) Rapid drug-membrane binding screen. A compartmentalised, rapid drug screening device will allow parallel measurements of drug interactions with a number of artificial plasma membrane mimics (PMMs) formed by an array of parallel droplet interface bilayer or vesicle networks.iii) In-Cubo Crystallization of Large Membrane Proteins. Learning how to swell lipid cubic phases will unlock our ability to construct cubic scaffolds with unit cell dimensions of the order of tens or hundreds of nanometres, allowing incorporation of large membrane proteins (>50kD), which are major drug targets for the pharmaceutical industry.Further biological and biotechnological applications will be developed during the course of the Programme by the current Investigators and a wider group of industrial and academic collaborators, who will be brought into the Programme as appropriate.

生物膜是大多数生物功能的核心，脂质膜在生物技术和纳米医学中越来越多地得到广泛的新应用。这种自组装的两亲界面可以采用一系列惊人的复杂形状和液晶结构，这些形状和液晶结构在 1、2 或 3 维中有序，长度范围从 2 - 3 纳米到微米。在分子水平上了解界面结构、有序、动力学和微观力学如何依赖于化学结构和组成以及温度、水合作用和压力等热力学变量，是学习如何操纵这种自组装软材料的关键接口来创建新颖且有用的结构和新技术，这是该计划的主要目标。我们已经确定了三个关键的基础科学挑战：1）不对称； 2）图案化； 3）曲率、长程组织和对称性。这些挑战背后有四个主要方面，我们认为这些方面至关重要：i）双层两亲物触发器的组成不对称性和动力学； ii) 横向偏析、线张力和微区形成； iii) 膜曲率和曲率弹性； iv) 脂质头基之间的电荷和偶极相互作用。此外，这四个方面之间存在着复杂的耦合，这是我们将重点关注的地方。我们组建了一个由五个领先的英国大学研究小组组成的团队，涵盖化学、物理和生物物理学。这些小组拥有互补的专业知识，涵盖实验室和同步加速器时间分辨 X 射线衍射、中子散射、固态核磁共振、量热法、生物分子力显微镜、朗缪尔槽和微流体技术、线性和非线性光谱、原子力显微镜、光谱和光学成像、光镊、微流变学和理论。这些方法将用于应对三个关键基础科学挑战的不同相互关联的方面。我们将通过严格监管的管理结构以及五个研究小组之间的定期会议和人员交流，确保所有研究结果的有效转化和综合。基于该计划之前开发的工程规则和技术，我们将将早期开发脂质结构的工作整合到活性脂质系统中，例如：水中的自封装液滴界面双层网络；确定尺寸的图案化不对称囊泡：将微流体与智能液滴微型工具耦合；然后，我们将利用这些知识开发三个演示系统：i) 人工细胞器。模仿生物学的一些显着功能和特性的人工细胞器机器的发展将带来个性化医疗保健的新方法。 ii) 快速药物膜结合筛选。分隔的快速药物筛选装置将允许并行测量药物与由平行液滴界面双层或囊泡网络阵列形成的许多人造质膜模拟物（PMM）的相互作用。iii）大膜蛋白的立方内结晶。学习如何膨胀脂质立方相将解锁我们构建单位细胞尺寸为数十或数百纳米数量级的立方支架的能力，从而允许掺入大膜蛋白（> 50kD），这是制药行业的主要药物靶点。目前的研究人员和更广泛的工业和学术合作者群体将在该计划期间开发进一步的生物和生物技术应用，这些合作者将酌情纳入该计划。

项目成果

Machine learning platform for determining experimental lipid phase behaviour from small angle X-ray scattering patterns by pre-training on synthetic data

机器学习平台，用于通过对合成数据进行预训练，从小角度 X 射线散射模式确定实验脂质相行为

• DOI: http://dx.10.1039/d1dd00025j
• 发表时间: 2022
• 期刊: Digital Discovery
• 作者: Abdel Aty H

The effect of headgroup methylation on polymorphic phase behaviour in hydrated N -methylated phosphoethanolamine:palmitic acid membranes

头基甲基化对水合N-甲基化磷酸乙醇胺:棕榈酸膜多晶型相行为的影响

• DOI: http://dx.10.1039/d1sm00178g
• 发表时间: 2021
• 期刊: Soft Matter
• 影响因子: 3.4
• 作者: Allen M

The Venom that Packs a Punch for Cancer

对抗癌症的毒液

• 发表时间: 2015
• 期刊: Laboratory News
• 作者: Aufderhorst

Membrane Adhesion through Bridging by Multimeric Ligands.

通过多聚配体桥接实现膜粘附。

• DOI: 10.1021/acs.langmuir.6b03692
• 发表时间: 2017-01-24
• 期刊: Langmuir : the ACS journal of surfaces and colloids
• 作者: O. Amjad;B. Mognetti;P. Cicuta;L. Di Michele
• 通讯作者: L. Di Michele

Melting transition in lipid vesicles functionalised by mobile DNA linkers

通过移动 DNA 连接器功能化的脂质囊泡的熔化转变

• DOI: http://dx.10.48550/arxiv.1608.05788
• 发表时间: 2016
• 作者: Bachmann S