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

CBET-0828046I。Szleifer，西北大学众所周知，细胞膜形成结构域，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。受这些生物环境局部分离以优化功能的能力的启发，该项目旨在在分子水平上了解如何驱动两亲分子混合物中的结构域形成，以设计可切换和选择性结合环境。拟议的工作涉及理论方法的开发和应用，这将使域形成的热力学和动力学的研究，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PI和合作者已经开发了20多年的分子理论的平衡和动力学版本。本文的工作主要分为三个部分：1）两亲性混合物的相行为预测，其中考虑了分子中含有和不含有聚合物头基的情况。2)在存在（和不存在）聚合物间隔区的情况下平衡配体-受体结合的系统研究。这些研究将进行的配体附着到表面的纳米粒子的球形和圆柱形的几何形状，以及平面表面/接口。3)选择性动力学研究：i）由环境变化驱动的两亲系统中结构域的形成; ii）配体-受体结合和iii）结构域形成后的配体-受体结合。拟议的系统研究将能够建立一般准则的表面和界面的优化设计，可以找到在生物材料，生物传感器和药物载体系统的应用程序，以及纳米粒子的表面改性，可以优化结合成像或separation.Intellectual优点：响应界面的最佳结合的分子设计结合了工程，物理，化学和生物学的多学科专业知识。所提出的工作具有双重目的的基本理解，然后可以应用于具有新的界面性质的材料的分子设计。这项工作结合了：1）对两亲分子与含有具有特定结合能力的化学部分的聚合物的复杂混合物的相行为、动力学和结构性质的基本理解。这种理解也可能揭示细胞膜中的组成-功能关系。2)研究结果可直接应用于生物材料、生物传感器和药物载体的合理设计。研究这些复杂的混合物需要了解平衡和时间依赖性。时间相关行为在时间上跨越许多数量级。因此，所提出的工作，结合原子模拟，是优秀的短时间尺度与时间相关的分子理论，使研究很长的时间保持分子水平的描述的混合物。与教授实验组的合作。汤普森（普渡大学），根策（NCSU）和沙尔（西北）将提供理论工作与现实检查在工作的所有阶段。更广泛的影响：拟议的工作将提供研究生和本科生的教育经验。PI计划利用西北大学现有的资源，吸引妇女和代表性不足的少数民族参加这一项目。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被整合到PI自加入西北大学工程学院以来正在开发的新课程中。这项研究的结果将发表在同行评议的期刊上，研究结果的流行版本将在PI的网站上提供。拟议的工作还包括软件的开发，以应用分子理论。这些程序可从PI的网站下载，由于拟议工作涉及大量多学科应用，因此将供非专家使用。

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.