A Blockcopolymer Strategy Towards Synthetic Ubiquitin

New York University, New York NY

Investigators

Abstract

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.