In this project funded by the Macromolecular, Supramolecular and Nanochemistry Program of the Chemistry Division, Timothy Deming of the University of California at Los Angeles will study how to utilize different types of initiation chemistries and polymerization catalysts in one reaction to generate branched polypeptide architectures ranging from cylindrical brush to hyperbranched. The approach is to employ different initiation chemistry, different monomers (N-carboxyanhydrides and their sulfur derivatives), and different nickel and cobalt polymerization catalysts to control the relative initiation rates of the added free initiator versus ones that are tethered to the side chain of the monomer. In this manner, a range of polymer architectures can be prepared by controlling the amount of propagation that occurs from each type of initiating site. The broader impacts involve advancing teaching, training and learning in interdisciplinary bioengineering at UCLA as well as participating in recruiting underrepresented minorities to pursue advanced STEM degrees.
This work will enhance our fundamental understanding about how to easily prepare polypeptides, the basic component of proteins, which have different types of branched structures. The results of these studies could have many important long term impacts on applications in which protein-based materials are important, including drug delivery, tissue engineering, and other areas of biotechnology.
Many natural structural materials found in the body are made of polymers with branched chain architectures. Important examples are the mucins and other polysaccharide-protein hybrid materials that play important roles in maintaining proper cell function and in lubrication of joints. Branched chain polypeptides have shown great potential since their abundance of functional groups, and three-dimensional globule-like presentation of functionality, makes them attractive for biomedical applications such as antigen presentation in vaccines, magnetic resonance imaging (MRI) contrast agents and as drug carriers. Since current synthetic methods for preparation of branched chain polypeptides require expensive and tedious stepwise synthesis or lack reproducibility and control, only a few, simple branched polypeptides have been prepared to date. Existing methods limit one’s ability to readily vary branching density or amino acid compositions in a series of samples, or to prepare more complex macromolecular structures that can mimic biological systems. The ability to readily prepare and tune such structures, the goal of this proposal, will open up new areas of research on the self-assembly and properties of such complex macromolecules. These new branched and hyperbranched copolypeptides combined with linear segments containing ordered secondary structural elements, such as b-sheets and a-helices, have tremendous potential to form hierarchical supramolecular assemblies that begin to rival the complex biopolymer assemblies found in nature. The key objectives of this project were to (i) use the selectivity of transition metal initiators to develop a robust methodology for the facile synthesis of branched copolypeptides, and (ii) develop methods for use of sulfur containing monomer building blocks to allow the facile preparation of copolypeptides with controlled branching density. Achieving these goals will require a detailed understanding of the polymerization catalysis, which will be achieved through mechanistic studies on the different chain initiation and propagation reactions. In this project, the PI has also been active in training graduate students and applying the concepts of this research in the classroom. The results of our studies resulted in 2 publications, with one additional paper in preparation. We developed a general method for synthesis of branched copolypeptides via catalysis which was published in the Journal of the American Chemical Society. We also published, in ACS Macro letters, a complimentary method to prepare brush copolymers via selective conjugation of polymer chains to a reactive main chain. Finally, our studies on sulfur containing monomers for polypeptide and brush polypeptide synthesis is nearing completion and we plan to publish this work in the near future. Over the course of this project, three graduate students were trained under this grant, one earned her PhD degree and is now working for Baxter Healthcare, one has recently completed his MS degree, and the third is completing the work for his PhD degree this summer. The students involved in this project gave presentations, such as at the American Chemical Society National Meeting. One student on this project, Allison Rhodes, also served as the head-TA for all the organic chemistry lab sections at UCLA last quarter, where she was involved in training new graduate students to TA, and developed her mentoring skills. To broadly disseminate their findings, students also attend at least one national ACS, MRS, or BMES meeting per year, and research findings were published in multidiscliplinary, high impact journals. In addition, 1 undergraduate student has also participated in this project. In addition to learning laboratory skills and some of the above-mentioned techniques, he also learned how to perform research and tackle open-ended problems. This student started graduate school in a Chemistry Ph. D. program in Fall 2010.
