The Organic and Macromolecular Chemistry Program in the Chemistry Division at the National Science Foundation supports Professor Samuel Gellman at the University of Wisconsin, who will synthesize new, conformationally constrained -amino acids and derivatives, and evaluate the conformation of oligomers that contain these new subunits. The present focus of this research involves basic synthetic and structural chemistry. Specific goals of the proposed research are to develop efficient synthetic routes to new conformationally constrained peptide building blocks and to study the conformational behavior of oligomers that contain constrained residues with the aim of identifying new and stable foldamer secondary structures. Interest in the development of synthetic foldamers has been kindled by recognition of the many important and complex functions carried out by precisely folded oligomers, especially proteins, in biological systems. The proposed activities will expand the scope of previous landmark studies by pursuing an emerging family of foldamer compounds, the gamma peptides and their hybrids.

Detailed understanding and research in synthetic foldamers will not only help to understand how biofoldamers fold and function but also enable the design of new materials with useful properties. The proposed foldamer research represents an excellent way to train young scholars for independent careers. Progress in this area demands applying a non-traditional combination of tools and concepts to areas as diverse as asymmetric organic synthesis and biophysical characterization of higher order molecular structure. Students who participate in this research, at the graduate or undergraduate levels, will emerge well-equipped to confront challenges in their independent careers. In addition, the proposed research offers an excellent basis for conveying to undergraduates in the classroom the essence, appeal, and significance of modern chemistry research. Specifically, this topic enables a lecturer to show how classical topics in organic reactivity and synthesis can be used to address new research challenges.

Project Report

This project is part of a long-term effort to develop entirely new classes of molecules that display unique and valuable functions. Such molecules should ultimately be useful in application areas of great importance to human society. For example, the molecular design strategy for which we are laying a foundation could someday provide new and powerful therapeutic agents for treating disease, or new diagnostic tools for detecting disease. Our approach is inspired by the the reliance of biological systems on large polymers to carry out complex functions. Polymers are molecules in which many subunits are linked together in a linear array. In most synthetic polymers, such as polystyrene, all the subunits are chemically identical. In contrast, most biopolymers contain different types of subunits; proteins, for example, contain 20 different subunits. A protein is defined by the sequence of subunits along the chain. In order to be functional, most proteins must fold into a specific three-dimensional shape. Folding brings specific subunits into precise arrangements, which are necessary for the biological activity. Our research focuses on synthetic polymers (or shorter versions, called oligomers) that are intended to fold into three-dimensional structures that are reminiscent of (but not necessarily identical to) those of proteins. This type of molecule is referred to as a "foldamer". We hypothesize that learning the rules that govern folding of new types of oligomers will ultimately allow us to endow such molecules with protein-like functions while avoiding some unfavorable properties of proteins themselves. One unfavorable property is susceptibility to rapid degradation in biological fluids, which hinders many biomedical applications of proteins, and which can be avoided by unnatural foldamers. This NSF grant enabled us to make very significant progress in our study of protein-inspired foldamers. The subunits in proteins themselves are derived from alpha-amino acids. With earlier NSF support, we pioneered the study of oligomers containing beta-amino acids instead ("beta-peptides"), and oligomers in which alpha- and beta-amino acid residues are combined ("alpha/beta-peptides"). During the current funding period we deepened our understanding of beta- and alpha/beta-peptide folding behavior. Some of this work emerged from a collaboration with researchers at Purdue University, who deployed very sophisticated structure-characterization tools. The most important feature of the research supported by this grant was the extention of our approach to foldamers containing gamma-amino acid subunits. We succeeded in learning how to synthesize new types of gamma-amino acids that were designed to manifest strong and specific folding tendencies. The realization of these folding tendencies was established via extensive physical characterzation. The "rules" governing the structural behavior of the new foldamers represent a contribution of high intellectual merit. Since our previous work has enabled us to generate alpha/beta-peptide foldamers with valuable activities, the new rules represent a broader impact of the most recent research, because these rules can be used by us and others for future function-based design efforts. Conducting this research provided excellent training for graduate students as independent scientists, which is a further facet of the work's broader impact.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Tyrone D. Mitchell
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University of Wisconsin Madison
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