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Thermodynamics of Metal-Protein Interactions

金属-蛋白质相互作用的热力学

基本信息

批准号：
1904705
负责人：
Dean Wilcox
金额：
$ 41.6万
依托单位：
Dartmouth College
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1904705&HistoricalAwards=false
关键词：
Thermodynamics Metal Protein Interactions

项目摘要

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Dean Wilcox from Dartmouth College to investigate the binding of charged metal particles (metal ions) to proteins as well as the properties of metal ions when they are bound to proteins. Essential metals (e.g., zinc, copper, iron) have beneficial properties for living organisms. Proteins play key roles in the import, transport, storage and export of these essential metals, as well as in the sequestration and removal of other metals that are toxic to living systems (e.g., mercury, lead, cadmium). Experiments that measure metal ion binding to proteins provide fundamental insight into how proteins select the essential trace metals and disregard or remove toxic metals. Experiments conducted by Dr. Wilcox's research group reveal how proteins tune the properties of metals for essential reactions. This knowledge is important because both beneficial and toxic metals have distinct reactivities when they are bound to a protein (e.g., metalloenzymes). The protocols and analysis developed in this research and the insight gained from these studies are valuable for biology and medicine. Students working at the interface of inorganic, biological and physical chemistry gain important knowledge and valuable skills for their careers in science and education, thereby enhancing the scientific workforce.This research seeks to quantify the thermodynamics of metal ions binding to proteins, to provide new insight into important biological processes, and to reveal how proteins modulate the redox properties of metal ions. First, the metal binding, which is the basis for biological function, is being investigated. The thermodynamics of the binding of mercury(II), methylmercury and related species to the Mer proteins in the bacterial mer pathway for mercury detoxification are being quantified to elucidate the mechanism of individual steps in this pathway. Other studies focus on the quantification of binding of copper(I) to the neuronal isoform of metallothionein, which is a protein involved in metal storage and sequestration in the brain, and to unique copper storage proteins (Csp's) in methane-metabolizing bacteria. In both cases, several metal ions bind to the protein. The mechanism of binding and release of these metal ions, including cooperativity, is being elucidated. Second, a protocol that determines the metalloprotein reduction thermodynamics from calorimetric measurements of metal binding, is being used to investigate selected metalloproteins and metalloenzymes for new insight into the protein modulation of the metal reduction potential. Several variants of azurin with higher and lower reduction potentials are being studied, as are selected copper enzymes. This method is being extended to studies of metalloenzymes involved in oxygen redox reactions, specifically superoxide dismutases that contain copper, iron or manganese. In addition to determining the redox thermodynamics of these metalloproteins, the thermodynamics and accompanying proton transfer of the two steps of the overall reaction, O2- oxidation and O2- reduction, are being quantified.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

有了这个奖项，化学部的生命过程化学项目资助达特茅斯学院的Dean Wilcox博士研究带电金属颗粒（金属离子）与蛋白质的结合以及金属离子与蛋白质结合时的性质。必需金属（例如，锌、铜、铁）对生物体具有有益的特性。蛋白质在这些必需金属的进口、运输、储存和出口中以及在对生命系统有毒的其他金属（例如，汞、铅、镉）。测量金属离子与蛋白质结合的实验为蛋白质如何选择必需的微量金属并忽略或去除有毒金属提供了基本的见解。Wilcox博士的研究小组进行的实验揭示了蛋白质如何调节金属的基本反应特性。这一知识很重要，因为有益和有毒金属在与蛋白质结合时具有不同的反应性（例如，金属酶）。在这项研究中开发的协议和分析以及从这些研究中获得的见解对生物学和医学都很有价值。在无机化学、生物化学和物理化学领域工作的学生将获得重要的知识和宝贵的技能，为他们的科学和教育事业奠定基础，从而增强科学人才队伍。本研究旨在量化金属离子与蛋白质结合的热力学，为重要的生物过程提供新的见解，并揭示蛋白质如何调节金属离子的氧化还原性质。首先，正在研究作为生物功能基础的金属结合。汞（II），甲基汞和相关物种的汞解毒细菌mer途径中的Mer蛋白质的结合的热力学正在量化，以阐明在这一途径中的各个步骤的机制。其他研究集中在定量铜（I）与金属硫蛋白的神经元同种型的结合，金属硫蛋白是一种参与大脑中金属储存和螯合的蛋白质，以及甲烷代谢细菌中独特的铜储存蛋白（Csp）。在这两种情况下，都有几种金属离子与蛋白质结合。这些金属离子的结合和释放机制，包括协同性，正在阐明。第二，一个协议，确定金属结合的量热测量的金属蛋白质还原热力学，被用来调查选定的金属蛋白质和金属酶的金属还原电位的蛋白质调制的新见解。正在研究具有较高和较低还原电位的天青蛋白的几种变体，以及所选择的铜酶。这种方法正在扩展到研究参与氧氧化还原反应的金属酶，特别是含有铜，铁或锰的超氧化物歧化酶。除了确定这些金属蛋白质的氧化还原热力学，热力学和伴随的质子转移的两个步骤的整体反应，O2-氧化和O2-还原，正在量化。这一奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。