Structural Biology
Developing rapid computational methods that can predict stabilizing mutations of proteins for gene-directed enzyme prodrug therapy (GDEPT). In GDEPT, a prodrug is activated in the tumor, with the consequence that damage to normal tissues is minimized. Prodrugs are chemicals that are nontoxic even at relatively high doses but can be converted to toxic substances by specific activating enzymes. Using this approach, the toxicity associated with chemotherapy can be reduced. To achieve this, new computational modeling technology will be developed to predict which site-directed mutations can result in enhanced stability of yeast cytosine deaminase, so that it can be delivered to the sites of human tumors and remain active at body temperature. This enzyme converts 5-fluorocytosine into the commonly used chemotherapeutic agent, 5-fluorouracil (5-FU). The ability to design mutations that stabilize proteins at higher temperatures will have broad applications to improve many medical and industrial products, including the enzymes used in detergents.
Research Team: R. Cukier (Chemistry), L. Kuhn (BMB) and H.Yan (BMB)
Developing methods for describing protein-protein/drug interactions on the wide range of length and time scales required for understanding signal transduction and cell regulation. Proteins such as kinases, which are mis-regulated in cancer and diabetes, undergo large conformational (shape) changes in the course of binding to their molecular partners. We will combine the ROCK methodology developed at MSU, which can capture kinase motions across the entire time scale relevant to their function, with molecular dynamics approaches, which can refine the structural and energetic assessment of these conformations, as the basis for designing new inhibitors to decrease the function of kinases. Another application will be to nucleotide-dependent switch proteins, which, in oncogenic mutant form, are found in about 25% of human tumors.
Research Team: R. Cukier (Chemistry), M. Feig (Biochemistry & Molecular Biology and Chemistry), L. Kuhn (Biochemistry & Molecular Biology), and W. Wedemeyer (Biochemistry & Molecular Biology and Physics)
Generating models of membrane proteins from experimental constraints and simulating membrane protein dynamics at multiple resolutions to elucidate their functional mechanisms and identify lipids likely to bind to such proteins and stabilize their structures. A key subject will be cytochrome c oxidase as a structurally defined model of a multi-subunit membrane protein. Recently, it was found that oxidase mutations are associated with increased rates of programmed cell death.
Research Team: R. Cukier (Chemistry), M. Feig (Biochemistry & Molecular Biology and Chemistry), S. Ferguson-Miller (Biochemistry & Molecular Biology), and W. Wedemeyer (Biochemistry & Molecular Biology and Physics)