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Protein Design by Dynamic Combinatorial Libraries

Our research goals are to elucidate the roles of amino acid side-chain packing in protein folding and stability using dynamic combinatorial libraries. As a starting point, we are synthesizing proteins of optimal stability. Our design strategy uses a directed self-assembly approach.

Peptide modules designed to adopt context-dependent secondary structure are allowed to associate to create higher order topologies. These topologies are defined by the covalent incorporation of metal ion-binding ligands into the peptide modules: the coordination requirements of the metal ions thus direct the ensemble number and orientation.

Kinetically labile metal/ligand systems allow participating modules to exchange under thermodynamic control. The resulting equilibrium population of metal-assembled proteins constitutes a dynamic combinatorial library, which is self-screening for stability. The dominant species at equilibrium are those which possess optimally packed and folded structures.

This is a fast, high-throughput technique for identifying lead sequences for de novo proteins.

The side-chain packing responsible for stabilizing protein cores is an instance of molecular recognition by which any side-chain is accomodated by those around it. We are extending this idea by designing proteins whose hydrophobic cores contain a patterned cavity that can recognize and bind small molecules. Such proteins can then be engineered to create recognition arrays on surfaces. In this way we hope to construct sensors for clinical and environmental diagnostic applications.