Samuel H. Gellman
Department of Chemistry
University of Wisconsin
1101 University Avenue
Madison, WI 53706
1988 Searle Scholar
Design of new polymers
We are broadly interested in developing new types of organic molecules that display useful functions. In addition, we seek to understand how proteins, the most diverse class of biomolecules, perform their natural functions. Our efforts require a wide range of experimental tools, including asymmetric organic synthesis, high-resolution NMR and crystallographic analysis of molecular structure, protein expression and biochemical assays.
Nature teaches us that folded oligomers can be very powerful molecular machines, as exemplified by proteins and nucleic acids. "Foldamers" are unnatural oligomers that adopt compact, specific and predictable shapes. The foldamer approach represents a new strategy for designing molecules that display specific functions. We are interested in developing foldamers that mimic the shapes of natural peptides or proteins, for biomedical applications, and in foldamers that adopt unprecedented shapes. Our efforts so far have focused on oligomers of beta-amino acids ("beta-peptides") and oligomers containing both alpha- and beta-amino acid residues ("alpha/beta-peptides"). We have shown that properly designed helix-forming foldamers can disrupt protein-protein interactions associated with viral infection or cancer. Recent publications describe these and other applications and our efforts to create foldamers that adopt specific quarternary structure. Long-term goals include generating foldamers with specific tertiary folding patterns and catalytic activities. Our foldamer research involves a substantial synthetic effort. We must develop efficient asymmetric routes to beta-amino acid building blocks. Looking forward, we are very interested to include gamma-amino acids among our foldamer subunits, which will require development of new methodology
New tools for studying the origins of protein folding preferences
We want to understand how the sequence of a protein determines the folding pattern adopted by the polypeptide chain. We have recently developed a new method for probing protein conformational stability, "backbone thioester exchange," and we are now employing this method to ask fundamental questions about the origins of protein folding preferences. For example, we are evaluating how helical segments pack against one another. We are applying this technique to one of the most profound challenges in protein structure, understanding the factors that control the folding and assembly of membrane proteins.
Design of biologically active polymers
We are exploring materials generated via ring-opening polymerization of beta-lactams. The resulting poly-beta-peptides (also known as nylon-3 polymers) have a protein-like backbone, which should make them biocompatible. We have recently shown that co-polymers in this class can mimic the selective antibacterial activity of natural peptide antibiotics. We are currently exploring polymers in this class as antimalarial agents, antifungal agents, lung surfactant mimics and scaffolds for tissue engineering. This work is highly collaborative.
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