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

生态旅游- 0828046 - i。众所周知，细胞膜形成结构域是为了开启和关闭细胞功能。例如，某些蛋白质只在富含胆固醇的区域吸附到膜上。受这些生物环境局部分离以优化功能的能力的启发，该项目旨在从分子水平上理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的环境。提出的工作包括理论方法的发展和应用，这将使研究结构域形成的热力学和动力学来优化或抑制配体-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。提出的工作分为三个部分：1)预测两亲性混合物的相行为，其中分子将考虑有和没有聚合物头基。2)系统研究在存在（或不存在）聚合物间隔剂的情况下配体与受体的平衡结合。这些研究将针对附着在球形和圆柱形纳米颗粒表面以及平面/界面上的配体进行。3)环境变化驱动下两亲体系结构域形成的选择性动力学研究；Ii)配体-受体结合和iii)结构域形成时配体-受体结合。提出的系统研究将能够为表面和界面的优化设计建立一般指导方针，可以在生物材料，生物传感器和药物载体系统中找到应用，以及纳米颗粒的表面修饰，可以优化成像或分离的结合。智力优势：反应界面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，即基本理解，然后可以应用于具有新型界面特性的材料的分子设计。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。这一认识也有助于揭示细胞膜的组成-功能关系。2)本研究成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。对这些复杂混合物的研究需要了解平衡和随时间变化的性质。时间依赖行为在时间上跨越了许多数量级。因此，提出的工作结合了短时间尺度的原子模拟和时间相关的分子理论，使研究能够在很长时间内保持混合物的分子水平描述。与教授实验小组的合作。Thompson（普渡大学）、Genzer （NCSU）和Shull（西北大学）将在工作的各个阶段为理论工作提供现实检查。更广泛的影响：建议的工作将为研究生和本科生提供研究教育经验。PI计划利用西北大学现有的资源，吸引妇女和未被充分代表的少数民族参与这个项目。这些资源包括由西北MRSEC管理的REU项目和夏季研究机会项目。这项工作的研究成果将被整合到PI加入西北大学工程学院后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，而研究结果的通俗版本将在PI的网站上提供。建议的工作还包括开发应用分子理论的软件。这些程序可以从PI的网站上下载，并且由于所提议的工作的大型多学科应用，将针对非专业人员使用。

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.