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建，折叠和组装小蛋白泛素的人工类似物。 泛素是一种存在于大多数生物组织中的调节蛋白，其细胞含有膜结合的细胞核。 基本上，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观生物中。 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，该项目将利用合成聚合物的折叠，其序列和二级结构与蛋白质中发现的相似。 嵌段共聚物将通过共价和非共价化学的组合来制备。 该项目中概述的两种不同策略将避免折叠并发症，同时允许观察不同和明确定义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折叠体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件。 这反过来又可能导致开发新型和可控的三维结构，作为电光，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。 研究团队将每月举办K-12内城学校的孩子，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。 一项由波特夫人寄宿高中的所有女孩参加的外联活动“STEM工作阴影体验”将使代表性不足的少数民族和女学生获得令人兴奋的职业机会。基于含有碳-碳键主链的合成聚合物制造人工蛋白质和酶，这些主链在活性和选择性方面与自然界的机械相媲美，并将这些三维结构用作重要应用的材料，长期以来一直是大分子化学中的挑战。 本计画将著重于聚芳异腈及聚对苯乙炔之合成与折叠，作为小分子蛋白质泛蛋白之结构类似物。 将采用两种不同的战略。 第一种策略将用于模拟泛素的主要结构元件，而第二种策略将专注于蛋白质二级结构的序列。 （共）聚合物将使用一套聚合技术制备，包括可逆加成-断裂链转移聚合（RAFT）、开环易位聚合（ROMP）和Pd-炔引发的异腈的活性聚合。 折叠的蛋白质样结构将通过一系列技术来表征，包括NMR、UV-Vis、荧光和CD光谱、X射线和光散射技术、AFM和STEM。 该项目将通过引入具有明确二级结构的嵌段共聚物、遥爪和杂遥爪嵌段共聚物以及功能性聚（对苯撑乙烯基）的新策略来创建一类新的蛋白质合成类似物并推进聚合物方法。 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和所得纳米结构的性质。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

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.