CAREER: atomistic characterization of protein-polymer conjugates

职业：蛋白质-聚合物缀合物的原子表征

• 批准号: 2339330
• 负责人: Matthew Eddy
• 金额: $ 64.3万
• 依托单位: University of Florida
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-05-01 至 2029-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2339330&HistoricalAwards=false
• 关键词: CAREER; atomistic; characterization; protein; polymer

Non-technical descriptionProtein-based materials have unique potential in both industrial and medical applications because they can be precisely tailored for specific tasks. However, the ability to fine-tune protein materials also makes them vulnerable to quickly falling apart and becoming useless. While proteins hold the promise to be powerful biological sensors or potent drugs able to treat a range of diseases, they often do not survive in the human body. The most promising method for making proteins more robust is to attach a polymer to them. This creates protein-polymer molecules that are joined together, where the polymer can shield the protein without changing its beneficial properties. This approach has led to several important drugs for treating inflammation and cancer. However, unlocking the potential to create many more biological materials or drugs made from protein-polymer conjugates has been very difficult. There are many different ways to build protein-polymer conjugates, with some being useful while others are not, and there is no guide for how they should be put together. The goal of this research is to advance the understanding of what makes some protein-polymer conjugates more robust and create rules so that they can be intentionally designed, which is crucial to unleashing their full potential as medicines, biological sensors, and new biological materials. The proposed research is integrated with an educational program that aims to provide an introduction and training on scientific techniques used to visualize proteins at the microscopic level as well as closely related scientific methods used to image the human body. The principle investigator will lead several hands-on workshops created for visits of high school and undergraduate students in partnership with the university precollegiate education and training center.Technical descriptionWhile protein-polymer conjugates are widely valued in materials research, their development is mostly empirical due to the lack of accurate molecular-level depictions of conjugates. The goal of this research is to experimentally provide atomistic descriptions of protein-polymer interactions that enhance the stability of conjugated proteins in biological materials. Conjugates are classified between two types based on their overall conformation and the degree to which the protein and polymer interact: ‘dumbbell’-like structures that are loosely connected or ‘shroud’-like structures that are more interwoven and show more persistent protein-polymer interactions. Macromolecular properties of the conjugated protein, including resistance to thermal and chemical denaturation, are expected to correlate with the three-dimensional conformation of the conjugate. It is hypothesized that the equilibrium between these two forms is determined by specific interactions between protein side chains and conjugated polymer. Conjugates exhibiting shroud-like interactions appear to possess unique and advantageous properties. The use of NMR will enable determination of the factors contributing to formation of shroud-like interactions and establish a set of quantitative principles for the design of protein-polymer conjugates with predictable properties. A deeper understanding of how polymers effectively stabilize proteins against thermal or chemical denaturation, will enable exploration of novel phenomena, such as leveraging polymer conjugation to rescue partially misfolded proteins and stabilize intractable proteins. Visualizing protein-polymer interactions at the atomistic level is crucial in unlocking the full potential of new polymer synthesis approaches and conjugation strategies, which are essential for utilizing biological materials in demanding environments.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

蛋白质材料在工业和医疗应用中具有独特的潜力，因为它们可以针对特定任务进行精确定制。 然而，微调蛋白质材料的能力也使它们容易迅速分解并变得无用。 虽然蛋白质有望成为强大的生物传感器或能够治疗一系列疾病的强效药物，但它们通常不能在人体内存活。 使蛋白质更坚固的最有希望的方法是将聚合物附着到它们上。 这创造了连接在一起的蛋白质聚合物分子，其中聚合物可以屏蔽蛋白质而不改变其有益特性。 这种方法已经导致了几种治疗炎症和癌症的重要药物。 然而，释放由蛋白质-聚合物缀合物制备更多生物材料或药物的潜力一直非常困难。 构建蛋白质-聚合物缀合物有许多不同的方法，其中一些有用，而另一些则没有，并且没有关于如何将它们组合在一起的指南。 这项研究的目标是推进对是什么使一些蛋白质-聚合物缀合物更强大的理解，并创建规则，以便它们可以被有意设计，这对于释放它们作为药物，生物传感器和新生物材料的全部潜力至关重要。 拟议的研究与一项教育计划相结合，该计划旨在介绍和培训用于在微观水平上可视化蛋白质的科学技术以及用于成像人体的密切相关的科学方法。 主要研究者将与大学预科教育和培训中心合作，领导几个为高中和本科生参观而创建的实践研讨会。技术说明虽然蛋白质-聚合物缀合物在材料研究中受到广泛重视，但由于缺乏精确的分子水平缀合物，它们的发展主要是经验性的。 本研究的目的是通过实验提供蛋白质-聚合物相互作用的原子描述，以提高生物材料中共轭蛋白质的稳定性。 结合物根据其整体构象和蛋白质与聚合物相互作用的程度分为两种类型：松散连接的“哑铃”状结构或更交织并显示更持久的蛋白质-聚合物相互作用的“哑铃”状结构。 结合蛋白的大分子性质，包括耐热性和化学变性性，预期与结合物的三维构象相关。 据推测，这两种形式之间的平衡是由蛋白质侧链和共轭聚合物之间的特定相互作用决定的。 表现出类双链相互作用的缀合物似乎具有独特和有利的性质。使用NMR将能够确定的因素，有助于形成类似的相互作用，并建立了一套定量的原则，蛋白质聚合物共轭物的设计与可预测的性能。 更深入地了解聚合物如何有效地稳定蛋白质对抗热或化学变性，将使探索新的现象成为可能，例如利用聚合物缀合来拯救部分错误折叠的蛋白质和稳定难处理的蛋白质。在原子水平上可视化蛋白质-聚合物相互作用对于释放新聚合物合成方法和缀合策略的全部潜力至关重要，这对于在苛刻的环境中利用生物材料至关重要。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。