Advancing Auto-Accelerated Helical Polymerization of Polypeptides Across Varied Systems

About This Grant

With the support of the Macromolecular, Supramolecular, and Nanochemistry Program in the Division of Chemistry, Dr. Yao Lin of the University of Connecticut will develop new strategies to synthesize synthetic polypeptides, artificial protein-like polymers, under metal-free, auto-catalyzed conditions. These polypeptides hold potential for wide-ranging applications such as biocompatible polymers, advanced medical therapeutics, and self-assembling materials, yet existing methods often demand specialized catalysts or extensive purification, which limits their application. By refining a process called “helix-guided polymerization”, this project will enable more efficient and finely controlled synthesis, including robust beta-sheet-forming variants that expand the type of polypeptides that can be produced and broaden their applications. Graduate and undergraduate students will receive training in advanced polymer synthesis and computational modeling, gaining multidisciplinary expertise. To promote broader collaboration and accelerate discovery, the project team will provide an online platform for kinetic analysis and partner with high school enrichment programs, thereby engaging the next generation of learners in cutting-edge polymer research. Altogether, these efforts will lead to more sustainable and accessible methods for producing protein-like polymers, stimulating fresh ideas and solutions within macromolecular research and STEM education. Technically, this research addresses major limitations in amino acid N-carboxyanhydride (NCA) polymerization, particularly sensitivity to impurities and limited control over beta-sheet formation, through an auto-accelerated ring-opening mechanism using a “sergeants-and-soldiers” strategy. Here, alpha-helical macroinitiators act as “sergeants” to guide the rapid and precise polymerization of beta-sheet-prone (and other) NCA “soldier” monomers. The project will systematically expand helix-guided polymerization to a broader set of beta-sheet-forming NCAs, develop an enzyme-like kinetic model capable of predicting copolymerization outcomes (including potential off-pathway or inhibitory effects), and establish techniques for direct polymerization from non-purified NCAs. This comprehensive approach expands the scope of NCA-based syntheses, removing the need for rigorous purification and enabling large-scale, metal-free polypeptide production. Ultimately, advanced macromolecular/supramolecular design and robust kinetic analysis will deepen the fundamental understanding of auto-catalyzed NCA polymerization, facilitating the creation of functional biopolymers for diverse applications in macromolecular, supramolecular, and nanomaterials research. 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.