1. Design of new polymers with well-defined folding properties ("foldamers"). Both RNA and proteins can adopt a wide range of compact and well-defined "tertiary structures." These folding propensities undoubtedly underlie Nature's use of these two polymers as catalysts. We are trying to design new polymer backbones that adopt highly ordered conformations. Once we have identified backbones that display long-range conformational order in solution, it should be possible to generate recognition and/or catalytic functions via combinatorial synthesis and screening methods.

Our current efforts focus on oligomers of b-amino acids ("b-peptides"). Computer-based design methods have allowed us to identify b-peptide segments that favor helical, sheet or reverse turn secondary structures; thus, all of the secondary structure types observed in proteins can be created with the unnatural b-peptide backbone as well. b-Peptide secondary structures appear to be very stable. We have recently shown via two-dimensional NMR studies that a b-peptide containing just six residues adopts a very stable helical conformation in aqueous solution. We are currently trying to create b-peptide tertiary structures, and to identify b-peptides with useful biological activities. We are also exploring other types of backbones.

2. Protein design: creation and analysis of b-sheets. We have developed a strategy for inducing formation of small b-sheets in aqueous solution. These systems are being used to probe the network of forces that control b-sheet conformational stability. For example, we have used b-sheet model systems to demonstrate length-dependent cooperativity in antiparallel b-sheet formation. It is well known that a-helices become more stable as they grow longer, but this question had not previously been addressed for b-sheets. Length-dependent cooperativity is strictly one-dimensional in a helix, but two dimensions of cooperativity are possible in a sheet (along the strands and perpendicular to the strands). We have shown that cooperativity occurs in both dimensions in aqueous solution.

3. Fundamental studies of noncovalent interactions. Understanding biological function at the molecular level requires an intimate knowledge of the way in which networks of noncovalent interactions control structure. Comprehension in this area is still quite limited: no one can predict a detailed protein folding pattern from an amino acid sequence, or design an effective inhibitor for a given enzymatic active site from first principles. We elucidate the conformation-directing roles of noncovalent interactions by characterizing the folding processes of carefully designed small molecules. Covalent linkage allows us to control which groups come together in solution. This strategy has allowed us to address fundamental biostructural questions. We have recently used this approach to analyze three-center ("bifurcated") hydrogen bonds, and nucleotide base stacking interactions.

4. Protein-amphiphile interactions: teaching small molecules to shepherd biopolymers. Use of a given protein for basic biochemical research or for biotechnological applications requires control over that protein's conformation and aggregation state. Many proteins are isolated in chemically denatured states, and they must be coaxed back to their natural folding patterns before they can be put to work. In the test tube, refolding is often unsuccessful because of competing aggregation. Living cells overcome this difficulty by employing "chaperone proteins" that guide other proteins to their properly folded forms. We have recently invented a technique for refolding in which small molecules ("artificial chaperones") promote renaturation of target proteins. In a related effort, we are currently trying to create small molecules that can promote crystallization of membrane proteins.

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