PEGylation and mutagenic manipulation of Hb and their combination are strategies actively being explored for their potential in generating Hb based oxygen carriers (HBOCs). These modifications are being implemented in an attempt to develop materials that minimize vasoactivity and the production of toxic reactants while maintaining adequate oxygen delivery to tissues. How these modification strategies alter the properties of Hb on a molecular level has not been well addressed. Accordingly, we propose to explore the single and combined biophysical consequences of modifying Hb by PEGylation and mutagenic manipulation. Alterations of conformation on a local and global level, protein dynamics, ligand-binding kinetics, and reactions that affect the use of cell-free Hb as a blood substitute will be exposed and explored. The work will be conducted in two laboratories, those of Dr. Joel Friedman (AECOM), and of Dr. Celia Bonaventura (Beaufort, Duke University). The modified Hbs under study will be examined under varied conditions to clarify underlying structure-function relationships. Hbs will be compared in solution, in sol-gels, and in trehalose glass under conditions that will enable us to identify differences in the heme environment and in energy barriers for ligand binding. Dr. Friedman's efforts will largely entail measurements of resonance Raman spectra, fluorescence, geminate recombination and other fast kinetic processes and transient absorption. Dr. Bonaventura's laboratory will characterize the same modified Hbs with regard to ligand (O2 and NO) binding cooperatively and responses to anionic effectors, formation and stability of S-nitrosated forms and alterations in SH reactivity, oxidative processes, using improved spectroelectrochemical methods and rapid-mixing methods. As an experienced and interactive team, Drs. Friedman and Bonaventura will dissect features of the basic control mechanisms that govern ligand entry and exit from the active site, the allosteric anionic control of heme and SH-group reactivity, and clarify the factors that govern the oxidative toxicity and NO-dependent interactions of HBOCs.
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