Heavy metal poisoning by elements such as mercury, lead, cadmium, and arsenic is a significant human health problem. Understanding the interaction of heavy metals with proteins is essential for defining the mechanism of toxicity, developing ways to minimize human exposure and to provide therapeutic regimens for removal of toxic ions. Our goals are (1) to develop peptide systems that provide a groundwork for the understanding of metalloregulatory proteins and metallochaperones, (2) to develop peptidic systems that can efficiently and selectively sequester heavy metal ions from aqueous solutions, and (3) to understand the thermodynamics and kinetics of metal binding to these designed peptides. To achieve these goals we will use a de novo peptide system based on the three-stranded coiled coil peptide aggregate motif that encapsulates with high affinity single heavy metal ions and provides spectroscopic models of mercury, cadmium and arsenic binding sites in biological systems. We will generate high resolution structures of this peptide system in the presence and absence of these heavy metals, elucidate the kinetic and thermodynamic mechanisms of heavy metal encapsulation, and expand the array of characterized systems to transition metal ions Fe(II), Cu(I), Ni(II), Co(II) and Zn(II). We will also extend the original design to include single chain peptides that encapsulate heavy metals and coiled coils that provide different coordination environments than the original design and those that encapsulate more than one heavy metal ion. These studies will expand the foundation of knowledge that has been laid by the scientific community investigating metallopeptide design, metalloregulatory proteins and heavy metal detoxification. These objectives will develop insight into the interplay between metal coordination and apopeptide structure in defining the overall metallopeptide fold, an important aspect of metallopeptide design. Also, development of highly efficient and specific heavy metal sequestering peptides could, ultimately, provide a viable and biodegradable means of removing heavy metals from contaminated water.
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