The studies proposed here have two long term objectives. The first is to understand how electrons are transferred in biological systems with high specificity, through the appropriate pathways and with rates that are consistent with metabolic requirements. The second is to understand how protein structures maintain their physiologically relevant tertiary structures in solution and the role of coupled dynamic processes. To accomplish these goals, a variety of approaches are used, focused on c-type cytochromes (principally), which are exploited as well characterized model systems. Thus, kinetic studies on electron transfer and protein dynamics are coupled with structural analysis (x-ray crystallography, NMR and modeling), thermodynamics, site directed mutagenesis, and genetics when appropriate.
Four specific aims are addressed. I. Defining the surface domains on cytochromes which are responsible for simultaneous recognition and specificity in their various metabolic pathways. 2. Elucidating the molecular processes responsible for evolutionary conserved movements within a cytochrome molecule and the biological role of these dynamic processes. 3. Establishing the chemical and structural features that control the stability of c-type cytochromes, including but not limited to: hydrogen bond networks, the role of bound waters, nonpolar interactions and ligand-metal interactions. 4. Expanding our understanding of the varied roles of cytochromes in microbial physiology in order to establish the breadth of evolutionary adaptations in recognition and specificity and thus to identify possible targets for drug intervention in pathogens. These studies, while addressing important issues in biological electron transfer, will also provide fundamental information on protein structure and function (recognition, stability, dynamics) that will be applicable to a wide range of biological processes.
Showing the most recent 10 out of 150 publications
