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

CBET-0828046I。Szleifer，西北大学已知细胞膜形成结构域以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。受到这些生物环境局部隔离能力的启发，为了优化功能，该项目旨在从分子水平上了解如何在两亲性分子的混合物中驱动结构域的形成，以设计可切换和选择性的结合环境。拟议的工作涉及理论方法的开发和应用，这些方法将能够研究结构域形成的热力学和动力学，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。工作分为三个部分：1)预测两亲性混合物的相行为，其中分子将考虑有或没有聚合物头基。2)系统地研究了存在或不存在聚合物间隔基时的平衡配基-受体结合。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)选择性动力学研究：i)环境变化驱动的两亲性体系中结构域的形成；ii)配体-受体结合和iii)配体-受体结合形成结构域。拟议的系统研究将能够建立可在生物材料、生物传感器和药物载体系统中找到应用的表面和界面的优化设计的一般指南，以及可以优化结合以用于成像或分离的纳米颗粒的表面修饰。智力优势：用于最佳结合的响应性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。这项拟议的工作具有基本理解的双重目的，然后可以应用于具有新界面特性的材料的分子设计。这项工作包括：1)对两亲性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了解。这一理解也可能有助于阐明细胞膜的组成-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。对这些复杂混合物的研究需要了解平衡性质和随时间变化的性质。这种依赖时间的行为在时间上跨越了许多数量级。因此，拟议的工作将在短时间尺度上出色的原子模拟与依赖时间的分子理论相结合，后者使研究非常长的时间保持了对混合物的分子水平描述。与教授的实验小组的合作。普渡大学的Thompson、NCSU的Genzer和西北大学的Shull将在工作的所有阶段为理论工作提供现实的检验。更广泛的影响：拟议的工作将为研究生和本科生提供研究性教育经验。国际和平协会计划利用西北大学现有的资源，吸引妇女和代表不足的少数族裔参与这一项目。这些资源包括由西北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加入西北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，研究结果的流行版本将在PI的网站上提供。拟议的工作还包括开发应用分子理论的软件。这些方案将可从国际和平研究所的网站下载，由于拟议工作涉及多学科的大量应用，这些方案的目的是供非专家使用。

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.