A Blockcopolymer Strategy Towards Synthetic Ubiquitin

在化学系大分子、超分子和纳米化学项目的支持下，纽约大学的Marcus Weck教授正在采用创新的化学设计原理来创造、折叠和组装小蛋白质泛素的人工类似物。泛素是一种调节蛋白，存在于含有膜结合细胞核的大多数生物体组织中。从本质上讲，这种蛋白质存在于许多大型单细胞生物和所有已知的非微生物中。复制泛素的化学结构和功能是非常复杂和繁琐的任务，因为合成方法需要以非常精确和序列控制的方式连接76个氨基酸。为了模拟泛素的结构复杂性，该项目将利用与蛋白质中发现的序列和二级结构相似的合成聚合物的折叠。嵌段共聚物将通过共价和非共价化学反应的结合来制备。项目中概述的两种不同的策略将避免折叠并发症，同时允许观察不同的和定义良好的大分子元素的相互作用。与该项目相关的研究可以将基于聚合物的文件夹科学提升到一个新的水平，并能够系统地研究蛋白质和酶的合成类似物的更大组装。这反过来可能导致新的和可控的三维结构的发展，作为光电、生物、生物医学、传感和基于计算机的应用的关键聚合物材料。研究小组将每月接待K-12市中心学校的孩子，并通过基本的动手实验和演示向他们介绍材料化学的兴奋。波特夫人寄宿高中的一项外展活动“STEM工作影子体验”将使未被充分代表的少数民族和女学生接触到令人兴奋的职业机会。长期以来，在大分子化学领域，基于含有碳-碳键基骨架的合成聚合物创造人工蛋白质和酶，在活性和选择性方面与大自然的机器相媲美，并将这些三维结构作为重要应用的材料，一直是一个挑战。本项目将重点研究聚（芳基异氰酸酯）s和聚（对苯基乙烯）s作为小蛋白泛素的结构类似物的合成和折叠。将采用两种不同的策略。第一种策略将用于模拟泛素的主要结构元素，而第二种策略将侧重于蛋白质的二级结构序列。（Co）聚合物将使用一系列聚合技术制备，包括可逆加成-破碎链转移聚合（RAFT）、开环复分解聚合（ROMP）和pd -炔引发的异氰化物活性聚合。折叠的蛋白质样结构将通过一系列技术进行表征，包括核磁共振、紫外-可见、荧光和CD光谱、x射线和光散射技术、原子力显微镜和STEM。该项目将创造一类新的蛋白质合成类似物，并通过引入具有明确二级结构的嵌段共聚物、远螺旋嵌段共聚物和异远螺旋嵌段共聚物以及功能聚对苯基乙烯的新策略，推进聚合物方法学的发展。此外，与这项工作相关的结果有可能增加对正交非共价相互作用的相互作用的理解，将合成聚合物折叠成三维结构，以及由此产生的纳米结构的性质。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。

With the support of the Macromolecular, Supramolecular and Nanochemistry program in the Division of Chemistry, Professor Marcus Weck of New York University is employing innovative chemical design principles to create, fold and assemble artificial analogs of the small protein ubiquitin. Ubiquitin is a regulatory protein that is found in most tissues of organisms whose cells contain a membrane-bound nucleus. Essentially, this protein is present in many large single-celled organisms and all known non-microscopic organisms. Replicating the chemical structure and function of ubiquitin is very complex and tedious task because the synthetic approach would require connecting 76 amino acids in a very precise and sequence-controlled manner. In order to mimic the structural complexity of ubiquitin, this project will utilize folding of synthetic polymers with sequences and secondary structures resembling those found in the protein. Block copolymers will be prepared through a combination of covalent and noncovalent chemistries. The two distinct strategies outlined in the project will circumvent folding complications while allowing observation of the interplay of different and well-defined macromolecular elements. The research associated with this project could move the science of polymer-based foldamers to the next level and enable systematic studies of larger assemblies of synthetic analogs of proteins and enzymes. This could in turn lead to the development of novel and controlled three-dimensional architectures as key polymeric materials for electrooptical, biological, biomedical, sensing and computer-based applications. The research team will host monthly K-12 inner city school children and introduce them to the excitement of materials chemistry through basic hands-on experiments and demonstrations. An outreach activity “STEM Job Shadowing Experience” with all-girls Mrs. Porter boarding high school will expose underrepresented minorities and female students to exciting career opportunities. Creating artificial proteins and enzymes based on synthetic polymers containing carbon-carbon bond-based backbones that rival nature’s machinery regarding activity and selectivity and to employ these three-dimensional architectures as materials for important applications has long been a challenge in macromolecular chemistry. This project will focus on the synthesis and folding of poly(aryl isocyanide)s and poly(p-phenylene vinylene)s as structural analogs of the small protein ubiquitin. Two distinct strategies will be employed. The first one will be used to emulate the main structural elements of ubiquitin, while the second strategy will focus on the sequences of the secondary structures of the protein. (Co)polymers will be prepared using a suite of polymerization techniques including reversible addition-fragmentation chain-transfer polymerization (RAFT), ring-opening metathesis polymerization (ROMP), and Pd-alkyne initiated living polymerization of isocyanides. The folded protein-like architectures will be characterized by a battery of techniques including NMR, UV-Vis, fluorescence, and CD spectroscopies, X-ray and light scattering techniques, AFM, and STEM. This project will create a new class of synthetic analogs of proteins and advance polymer methodology by introducing new strategies towards block copolymers with well-defined secondary structures, telechelic and heterotelechelic block copolymers, and functional poly(p-phenylene vinylene)s. Additionally, the results associated with this work have the potential to increase the understanding of the interplay of orthogonal noncovalent interactions to fold synthetic polymers into three-dimensional architectures and the properties of the resulting nanostructures.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.