Thermodynamics of Metal-Protein Interactions

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Dean Wilcox from Dartmouth College to quantitatively characterize the thermodynamics of metal ion binding to proteins. This research will provide insight in a) the contributions of metal ions to the stability of proteins, and b) the modulation by the proteins of the redox properties of bound metal ions. Using primarily microcalorimetry methods and systematic perturbations of the protein (site specific mutations) and of the metal (e.g., isostructural Zn2+, Co2+, Cd2+), the enthalpic and entropic components of the metal binding will be quantified, as will be the metal and the protein contributions to the stability of the metalloprotein. Additionally, the contribution of solvation to metal-protein interactions will be evaluated by determining solvent effects on the thermodynamics of metal binding to the protein. In a novel application of these methods, the thermodynamics of metal binding to a protein will be determined when the metal ions is in two oxidation states, and the enthalpic and entropic components of the metal reduction potential, which is modulated by the protein, will be quantified.Essential trace metals are normally bound to proteins in living organisms. The metals play crucial roles, including a structural role, where the metal (often zinc) helps to stabilize the active form of a protein, and a catalytic role in essential reaction, where the protein tunes the chemical properties of a metal (such as copper). Both the stabilization of a protein by a metal and the influence by a protein of the properties of metal ion will be quantified with experimental methods and analysis pioneered by Wilcox and his students. The proposed research will seek insight in the prevalence, placement and importance of so-called structural metals in proteins; this insight may guide the engineering of metal ions into therapeutic proteins for enhanced stability. Conversely, the identification of the features of a protein that influence the properties of a bound metal will help us to understand how Nature controls and uses the unique reactions of metals. Students working on this project gain extensive knowledge at the interface between inorganic, physical and biochemistry and learn skills important for careers in science and education.