Control of interfacial behavior through lipid domain formation, ligand-receptor binding and their synergetic effect

通过脂质域形成、配体-受体结合及其协同效应控制界面行为

• 批准号: 0828046
• 负责人: Igal Szleifer
• 金额: $ 30万
• 依托单位: Northwestern University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0828046&HistoricalAwards=false
• 关键词: Control; interfacial; behavior; through; lipid

CBET-0828046I. Szleifer, Northwestern UniversityCell membranes are known to form domains in order to switch on and off cellular function. For example certain proteins adsorb to membranes only in cholesterol rich domains. Inspired by the ability of these biological environments to locally segregate in order to optimize function this project aims to understand at the molecular level how to drive domain formation in mixtures of amphiphilic molecules in order to design switch able and selective binding environments. The proposed work involves the development and applications of theoretical approaches that will enable the study of the thermodynamics and kinetics of domain formation to optimize or inhibit ligand-receptor binding. The theoretical methodologies will include atomistic molecular dynamics simulations and the equilibrium and kinetic version of a molecular theory that the PI and collaborators have been developing for more that 20 years. The proposed work is divided into three parts: 1) Prediction of the phase behavior of amphiphilic mixtures, where the molecules will be considered with and without polymer head-groups. 2) Systematic study of the equilibrium ligand-receptor binding in the presence (and absence) of polymeric spacers. These studies will be carried out for ligands attached to the surface of nanoparticles of spherical and cylindrical geometries as well as to planar surfaces/interfaces. 3) Selective kinetic studies on: i) the formation of domains in amphiphilic systems driven by changes in the environment; ii) ligand-receptor binding and iii) ligand-receptor binding upon domain formation. The proposed systematic studies will enable to build general guidelines for the optimal design of surfaces and interfaces that can find applications in biomaterials, biosensors and drug carrier systems as well as the surface modification on nanoparticles that can optimize binding for imaging or separations.Intellectual Merit: The molecular design of responsive interfaces for optimal binding combines multidisciplinary expertise in engineering, physics, chemistry and biology. The proposed work has the dual purpose of fundamental understanding that can then be applied in the molecular design of materials with novel interfacial properties. The work combines: 1) the fundamental understanding of the phase behavior, kinetic and structural properties of complex mixtures of amphiphilic molecules with polymers containing chemical moieties with specific binding capabilities. This understanding may also shed light on the composition-function relationship in cell membranes. 2) The findings from this work can be directly applied in the rational design of biomaterials, biosensors and drug carriers. The study of these complex mixtures requires the understanding of equilibrium and time dependent properties. The time dependent behavior spans over many orders of magnitude in time. The proposed work, thus, combines atomistic simulations that are excellent for short time scales with time dependent molecular theory that enables the study of very long times maintaining a molecular level description of the mixtures. The collaboration with the experimental groups of Profs. Thompson (Purdue), Genzer (NCSU) and Shull (Northwestern) will provide the theoretical work with realistic checks at all stages of the work.Broader Impact:The proposed work will provide research educational experiences for graduate and undergraduate students. The PI plans to use the resources available at Northwestern University to attract women and underrepresented minorities to participate in this project. These resources include the REU program administered by Northwestern MRSEC and the Summer Research Opportunity Program. The research outcomes of the proposed work will be integrated into the new courses that the PI is developing since joining the engineering school at Northwestern. The findings from the research will be published in peer-reviewed journals and a popular version of the findings will be available in the PI's web site. The proposed work also includes the development of software to apply the molecular theory. The programs will be available for download from the PI's web site and will be aimed for the use by non-expert due to the large multidisciplinary application of the proposed work.

CBET-0828046I。已知西北大学病房的Szleifer膜形成域，以打开和关闭细胞功能。例如，某些蛋白质仅在富含胆固醇的结构域中吸附到膜上。受这些生物环境在局部分离以优化功能的能力的启发，该项目旨在在分子级别了解如何在两亲性分子的混合物中驱动域形成，以设计开关和选择性的结合环境。提出的工作涉及理论方法的发展和应用，这些方法将使域形成的热力学和动力学研究以优化或抑制配体受体结合。理论方法将包括原子分子动力学模拟以及分子理论的平衡和动力学版本，即PI和合作者已经开发了20年。提出的工作分为三个部分：1）两亲混合物的相行为的预测，其中分子将在有或没有聚合物头组的情况下考虑。 2）在聚合垫片的存在（和不存在）的情况下，系统研究配体受体结合。这些研究将针对连接到球形和圆柱几何形状以及平面表面/界面的纳米颗粒表面的配体进行。 3）关于以下方面的选择性动力学研究：i）由环境变化驱动的两亲动系统中域的形成； ii）配体受体结合和iii）配体受体对结构域形成的结合。拟议的系统研究将使可以在生物材料，生物传感器和药物载体系统中找到应用的表面和界面的最佳设计，以及在纳米颗粒上的表面修饰，以优化成像或分离的粘合。生物学。所提出的工作具有基本理解的双重目的，然后可以将其应用于具有新型界面特性的材料的分子设计中。工作结合了：1）对两亲性分子的复杂混合物的相对相，动力学和结构特性的基本理解与含有具有特定结合能力的化学部分的聚合物。这种理解也可能阐明细胞膜中的组成功能关系。 2）这项工作的发现可以直接应用于生物材料，生物传感器和药物载体的合理设计中。对这些复杂混合物的研究需要了解平衡和时间依赖性的特性。时间依赖的行为跨越了许多数量级。因此，提出的工作结合了原子模拟，这些模拟在短时间尺度上非常出色，并与时间依赖的分子理论相结合，可以研究长时间维持混合物的分子水平描述。与教授实验组的合作。汤普森（Purdue），Genzer（NCSU）和Shull（Northwestern）将在工作的各个阶段为理论工作提供现实的检查。BROADERIMPACT：拟议的工作将为研究生和本科生提供研究教育经验。 PI计划利用西北大学可用的资源来吸引妇女和代表性不足的少数民族参加该项目。这些资源包括西北MRSEC管理的REU计划和夏季研究机会计划。拟议工作的研究成果将集成到自加入西北工程学校以来PI开发的新课程中。研究结果将在经过同行评审的期刊上发表，并且该发现的流行版本将在PI的网站中获得。拟议的工作还包括开发软件以应用分子理论。该程序将可从PI的网站下载，并且由于拟议的工作的大量多学科应用，将针对非专家使用。