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Programmable 2- and 3-Dimensional Protein Assemblies

可编程 2 维和 3 维蛋白质组装体

基本信息

批准号：
2004558
负责人：
Faik Tezcan
金额：
$ 52.5万
依托单位：
University of California-San Diego
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2004558&HistoricalAwards=false
关键词：
Programmable Dimensional Protein Assemblies

项目摘要

Nontechnical SummaryWhether for constructing complex biological devices like enzymes or for building sophisticated materials with advanced physical properties like skeletal muscles, proteins have been nature’s premier building blocks throughout the course of evolution. Yet, the ability of laboratory scientists to control the self-assembly of proteins or to use them as synthetic building blocks to generate new functions has been severely limited. The overarching goal of the proposed research program is to overcome this limitation by developing new protein design tools based on metal coordination chemistry and DNA nanotechnology. In one project goal, the PI’s group will construct complex, cage-like protein architectures which can ultimately be used to encapsulate and release molecular cargo in a stimuli-dependent fashion. In a second project goal, they will exploit the programmability of DNA self-assembly to generate multicomponent protein architectures and elucidate the complex energy landscape of protein-DNA interactions. In terms of the broader impacts, the proposed effort will not only provide fundamental insights into biological self-assembly processes, but also lend access to novel protein-based functionalities and materials with potential applications in bio/nano-technology and basic sciences (e.g., separations, catalysis, delivery, sensing, X-ray or electron-diffraction-based structure determination). Due to its highly interdisciplinary nature, this project will provide an expansive training ground for graduate, undergraduate, and high school researchers, and help them tackle complex scientific problems later in their careers. As a new educational activity, the PI’s lab will start hosting STEM activities designed for Junior Reserve Officers’ Training Corps from San Diego-area high schools. These activities collectively will enhance the students’ understanding of proteins as biomolecules and their self-assembly/crystallization as well as their novel uses as building blocks for novel catalysts and materials. Importantly, the students will be exposed to daily activities that are taking place in a research laboratory. Technical SummaryWhile natural evolution has produced remarkable protein-based machines and materials over the course of billions of years, it has only explored an infinitesimally small fraction of the design/self-assembly space that could be achieved with the available protein folds. Therefore, it would be highly desirable to have the ability to craft ordered protein assemblies from scratch using building blocks of choice, which would greatly broaden the structural and functional scope of naturally existing protein assemblies and bioinspired materials. Previous findings from the PI’s indicate that the tools and principles of supramolecular/inorganic/polymer chemistry and protein engineering can be combined in new ways to address outstanding issues in protein self-assembly and to create novel biomaterials. In the proposed research, these efforts will be expanded under two Objectives. Under Objective 1, the PI’s group will expand their inorganic chemical toolkit through the use of unnatural metal chelating functionalities and combine them with computational design to access complex, stimuli-responsive polyhedral architectures that were previously out of reach. Objective 2 will exploit the programmability of DNA self-assembly to generate heteromeric/multicomponent protein architectures and to better understand the complex energy landscape of protein-DNA co-assembly. The Objectives will take advantage of two protein building blocks (cytochrome cb562 and Rop) to access a multitude of oligomeric and polymeric protein assemblies in a modular fashion, probe their structures and structural dynamics using state-of-the-art tools (e.g., cryoEM, X-ray diffraction and scattering), and examine their emergent functions (e.g., nucleic acid encapsulation).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.

无论是构建像酶这样复杂的生物装置，还是构建像骨骼肌这样具有高级物理特性的复杂材料，蛋白质在整个进化过程中一直是大自然的首要基石。然而，实验室科学家控制蛋白质自组装或将其用作合成构件以产生新功能的能力受到严重限制。提出的研究计划的总体目标是通过开发基于金属配位化学和DNA纳米技术的新的蛋白质设计工具来克服这一限制。在一个项目目标中，PI的团队将构建复杂的，类似笼子的蛋白质结构，最终可以用于封装和释放分子货物，以刺激依赖的方式。在第二个项目目标中，他们将利用DNA自组装的可编程性来生成多组分蛋白质结构，并阐明蛋白质-DNA相互作用的复杂能量景观。就更广泛的影响而言，所提出的努力不仅将提供对生物自组装过程的基本见解，而且还将提供在生物/纳米技术和基础科学（例如，分离，催化，传递，传感，x射线或基于电子衍射的结构测定）中具有潜在应用的新型基于蛋白质的功能和材料。由于其高度跨学科的性质，该项目将为研究生、本科生和高中研究人员提供广阔的训练场地，并帮助他们在以后的职业生涯中解决复杂的科学问题。作为一项新的教育活动，PI的实验室将开始为圣地亚哥地区高中的初级预备役军官训练团举办STEM活动。这些活动将提高学生对蛋白质作为生物分子及其自组装/结晶的理解，以及它们作为新型催化剂和材料的新用途。重要的是，学生将接触到在研究实验室中进行的日常活动。虽然经过数十亿年的自然进化已经产生了基于蛋白质的机器和材料，但它只探索了可用蛋白质折叠可以实现的设计/自组装空间的极小部分。因此，有能力使用选择的构建块从零开始制作有序的蛋白质组件将是非常可取的，这将大大拓宽天然存在的蛋白质组件和生物启发材料的结构和功能范围。PI的先前发现表明，超分子/无机/聚合物化学和蛋白质工程的工具和原理可以以新的方式结合起来，以解决蛋白质自组装中的突出问题，并创造新的生物材料。在拟议的研究中，这些努力将根据两个目标加以扩大。在目标1下，PI的团队将通过使用非自然金属螯合功能来扩展他们的无机化学工具包，并将其与计算设计相结合，以访问复杂的、刺激响应的多面体结构，这些结构以前是无法实现的。目标2将利用DNA自组装的可编程性来生成异质/多组分蛋白质结构，并更好地理解蛋白质-DNA共组装的复杂能量景观。目标将利用两种蛋白质构建模块（细胞色素cb562和Rop）以模块化方式访问大量寡聚和聚合蛋白质组件，使用最先进的工具（例如低温电镜，x射线衍射和散射）探测其结构和结构动力学，并检查其紧急功能（例如核酸封装）。该奖项反映了美国国家科学基金会的法定使命，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。