A supplement to: NIGMS 1R15GM144907-01A1 - Polymer-Lipid Particles investigated by Magnetic Resonance Spectroscopy

NIGMS 1R15GM144907-01A1-聚合物-脂质颗粒的补充 磁共振波谱研究 答复：PA-20-272--对现有NIH补助金和 合作协议(家长管理支持临床试验可选) 向NIGMS申请资金以获得最先进的凝胶渗透性 层析(GPC)多角度光散射(MALS)设备方便 聚合物分析。新型聚合物的开发是NIGMS 1R15GM144907- 因此，拥有可靠的表征聚合物的方法对于 这个项目。正在申请资金以获得Tosoh EcoSEC精英，包括 折射率与LenS3多角光散射探测器GPC MALS系统 能够高效、准确地进行聚合物分析，以取代2014年的设备。 项目摘要/摘要：膜蛋白约占所有蛋白质的30% 已知的蛋白质，但只有大约1%的蛋白质结构已解决。尽管最近 膜蛋白结构生物学方法的研究进展 重要的一类蛋白质落后于其可溶的同类蛋白质。膜蛋白是 对健康的许多方面至关重要，从调节细胞功能到 进入和离开细胞，通过使用膜蛋白的病毒感染 作为感染循环的一部分。在几乎90%的新开发和批准的 治疗学，蛋白质结构信息被用来指导发展 治疗分子。由于结构信息有限且不完整， 膜蛋白，靶向治疗和治疗的发展 膜结合蛋白是有限的。膜蛋白研究面临的挑战 结构是缺乏健壮和合适的类脂膜模拟物。现有 膜模拟物有可能阻碍膜蛋白结构的局限性 决心。这突显了开发脂膜模拟物的迫切需要 两者在两种结构上都提供了与天然脂双层很好的近似 和曲率，同时也有助于膜蛋白的结构分析 嵌入到模仿者中。然而，聚合物结构-功能关系并不是很好 为与脂质和膜蛋白相互作用的聚合物而建立的。 这个项目将使用现代受控聚合物化学工具，创建一个新的班级 能够与脂类自组装的聚合物。这些自组装的聚合物脂质 系统将在10纳米量级上形成定义良好的圆盘，从而提供脂质 膜模拟物适用于多种膜蛋白的分析。先进的 聚合物化学技术将能够微调聚合物的长度、电荷和 疏水性。通过GPC MALS进行的聚合物分析将提供有关 聚合物的性质、聚合物与聚合物之间的促进结构-功能关系 它们的自组装结构。聚合物还将使用自旋标签进行修饰 电子顺磁共振波谱。电子顺磁共振 光谱方法将用于聚合物、脂类和膜蛋白的修饰 使用适当的自旋标签，提供对局部动态和邻近的洞察 自组装的聚合物-脂和聚合物-脂-膜蛋白复合体。这些 这些见解可以用来指导聚合物的设计，以实现稳健的类脂膜模拟。 培训和指导本科生以及一名研究生助理将 是拟议项目的一个核心特点。本科生将全面融入 与研究生一起参与到项目中，包括聚合物分析，获得了 在材料科学和生物物理学的交界处掌握这一领域的技能。

A supplement to: NIGMS 1R15GM144907-01A1 - Polymer-Lipid Particles investigated by Magnetic Resonance Spectroscopy In response to: PA-20-272 - Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) Funds are requested from NIGMS to obtain state of the art gel permeation chromatography (GPC) multi-angle light scattering (MALS) equipment to facilitate polymer analysis. Development of novel polymers is integral to NIGMS 1R15GM144907- 01A1, therefore having reliable methods for characterizing the polymers is essential to the project. Funds are being requested to obtain a TOSOH EcoSEC Elite including Refractive Index and LenS3 Multi-Angle Light Scattering Detector GPC MALS system capable of efficient and accurate polymer analysis to replace equipment that is from 2014. Project Summary/Abstract: Membrane proteins represent approximately 30% of all known proteins but only approximately 1% of solved protein structures. Despite recent advances in methods for membrane protein structural biology, knowledge about this important class of proteins lags behind their soluble counterparts. Membrane proteins are critical to numerous aspects of health, ranging from regulation cellular function and transport into and out of the cell, through to viral infections which use membrane proteins as part of the infection cycle. In almost 90% of newly developed and approved therapeutics, protein structural information was used to guide the development of the therapeutic molecules. Due to the limited and incomplete structural information on membrane proteins, the development of therapeutics and treatments that target membrane bound proteins is limited. A challenge in elucidating membrane protein structures is the lack of robust and appropriate lipid membrane mimetics. Existing membrane mimetics have limitations that can hinder membrane protein structural determination. This highlights an urgent need to develop lipid membrane mimetics which both provide a good approximation to the native lipid bilayer in terms of both structure and curvature, while also facilitating structural analysis of the membrane protein embedded in the mimetic. Yet polymer structure-function relationships are not well established for polymers that interact with lipids and membrane proteins. This project will use modern controlled polymer chemistry tools, to create a new class of polymers that will self-assemble with lipids. These self-assembled polymer-lipid systems will form well defined discs on the order of 10s of nanometers, giving lipid membrane mimetics suitable for the analysis of many membrane proteins. The advanced polymer chemistry techniques will enable fine tuning of polymer’s length, charges, and hydrophobicity. Polymer analysis through GPC MALS will give detailed information on the polymer’s properties, facilitation structure -function relationships between polymers and their self-assembled structures. Polymers will also be modified with spin-labels for electron paramagnetic resonance spectroscopy. Electron paramagnetic resonance spectroscopy methods will be used on polymers, lipids and membrane proteins modified with appropriate spin labels, providing insights into the local dynamics and proximities of the self-assembled polymer-lipid and polymer-lipid-membrane protein complexes. These insights can be used to guide the design of polymers for robust lipid membrane mimetics. Training and mentoring of undergraduate students as well as a graduate assistant will be a core feature of the proposed project. Undergraduate students will be integrated fully into the projects, including the polymer analysis, along with the graduate student, gaining skills in this field at the interface of materials science and biophysics.