Martin A. Case

Bioorganic Chemistry

Assistant Professor

Martin.Case@uvm.edu
phone: 802-656-8246
office: Cook Rm A321

Broadly, 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. The strategy is thus 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.

Selected Publications

Mutz, M. W.; Case, M. A.; Wishart, J. F.; Ghadiri, M. R.; McLendon, G. L. "De Novo Design of Protein Function: Predictable Structure-Function Relationships in Synthetic Redox Proteins" J. Am. Chem. Soc. 1999, 121, 858-859.

Case, M. A.; McLendon, G. L.; "A Virtual Library Approach to Investigate Protein Folding and Internal Packing" J. Am. Chem. Soc. 2000, 122, 8089-8090.

Moffet, D. D.; Case, M. A.; House, J. C.; Vogel, K.; Williams, R.; Spiro, T. G.; McLendon, G. L.; Hecht, M. H. "Carbon Monoxide Binding by de novo Heme Proteins from a Designed Combinatorial Library" J. Am. Chem. Soc. 2001, 123, 2109-2115.

Wei, Y.; McLendon, G. L.; Hamilton, A. D.; Case, M. A.; Purring, C. B.; Lin, Q.; Park, H. S.; Lee, C.-S.; Yu, T. "Disruption of Protein-Protein Interactions: Design of a Synthetic Receptor that Blocks the Binding of Cytochrome c to Cytochrome c Peroxidase" Chem. Commun. 2001, 1580-1581.

Kipp, R. A.; Case, M. A.; Wist, A. D.; Cresson, C. M.; Carrell, M.; Griner, E.; Wiita, A.; Albiniak, P. A.; Chai, J. J.; Shi, Y. G.; Semmelhack, M. F.; McLendon, G. L. "Molecular Targeting of Inhibitor of Apoptosis Proteins Based on Small Molecule Mimics of Natural Binding Partners" Biochemistry, 2002 41, 7344-7349.

Gochin, M.; Khorosheva, V.; Case, M. A. "Structural Characterization of a Paramagnetic Metal-Ion-Assembled Three-Stranded alpha-Helical Coiled Coil" J. Am. Chem. Soc. 2002 124, 11018-11028.

Case, M. A.; McLendon, G. L.; Hu, Y.; Vanderlick, T. K.; Scoles, G. "Using Nanografting to Achieve Directed Assembly of de novo Designed Metalloproteins on Gold" Nano Lett. 2003 3, 425-429.

Cooper, H. J.; Case, M. A.; McLendon, G. L.; Marshall, A. G. "Electrospray Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometric Analysis of Metal-Ion Selected Dynamic Protein Libraries" J. Am. Chem. Soc. 2003 ASAP article.

Zheng, Y.; Case, M. A.; Wishart, J. F.; McLendon, G. L. "Do Main Chain Hydrogen Bonds Create Dominant Electron Transfer Pathways? An Investigation in Designed Proteins" J. Phys. Chem. B. 2003 ASAP article.