Toxic Metal Complexation by de Novo Designed Peptides

描述（由申请人提供）：汞、铅、镉和砷等元素引起的重金属中毒是一个严重的人类健康问题。了解重金属与蛋白质的相互作用对于确定毒性机制，开发最小化人类暴露的方法以及提供去除有毒离子的治疗方案至关重要。 我们的目标是（1）开发肽系统，为理解金属调节蛋白和金属伴侣蛋白提供基础，（2）开发肽系统，可以有效地和选择性地从水溶液中螯合重金属离子，（3）了解金属结合这些设计的肽的热力学和动力学。 为了实现这些目标，我们将使用从头肽系统的基础上的三链卷曲螺旋肽聚集体基序，封装高亲和力的单一重金属离子，并提供光谱模型的汞，镉和砷的生物系统中的结合位点。我们将产生高分辨率的结构，在这些重金属的存在和不存在下，这个肽系统，阐明重金属封装的动力学和热力学机制，并扩展阵列的特征系统过渡金属离子Fe（II），Cu（I），Ni（II），Co（II）和Zn（II）。我们还将扩展原始设计，以包括封装重金属的单链肽和提供与原始设计不同的配位环境的卷曲螺旋以及封装一种以上重金属离子的单链肽。 这些研究将扩大科学界调查金属肽设计、金属调节蛋白和重金属解毒所奠定的知识基础。这些目标将深入了解金属配位和载脂蛋白肽结构之间的相互作用，在定义的整体金属肽折叠，金属肽设计的一个重要方面。此外，开发高效和特异性的重金属螯合肽可以最终提供一种可行的和可生物降解的方法来去除污染水中的重金属。

DESCRIPTION (provided by applicant): 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.