HYDROGEN BONDING CAVITY MOTIFS ABOUT METAL IONS

描述(由申请人提供)：本提案研究的主要目的是确定金属蛋白中活性部位的结构与功能之间的基本关系。利用了一种生物启发的合成方法，结合了在活性中心中发现的结构成分，特别是那些控制金属离子(S)周围微环境(次级配位球)的结构成分。正在开发的有机化合物可以在结合的金属离子周围创建刚性结构，形成特定的微环境，模仿蛋白质活性位点中的模体。调节是通过非共价相互作用(例如氢键)实现的，这些作用战略性地放置在金属离子附近以影响功能；特别是与氧的结合和激活，这是与维持人类健康和衰老直接相关的过程。这些合成系统允许在非血红素金属酶中经常提出但很少观察到的高能瞬变的稳定：它们的检测为探索这些生物基本反应的机制方面提供了新的途径。长期目标包括发展金属辅助氧化催化的结构和功能关系。金属蛋白具有合成系统中尚未实现的功能。我们的假设是，缺乏对合成化合物中二次配位球的控制是实现预期功能的主要障碍。来自结构生物学的结果表明，金属蛋白二级配位球内的非共价相互作用在调节功能中起着重要作用。因此，与健康相关的金属蛋白的功能和功能障碍可以在其微环境变化的背景下被理解。即使在生物分子中，非共价相互作用如何能够影响金属介导的过程仍然不清楚。对这些影响的研究需要基础的反应性和机理研究，在这些研究中，可以单独分析单个组分的影响。我们已经开发了合成系统，通过它可以很容易地完成结构上的特定部位调节，为了建立与功能的相关性，这些类型的研究将导致对生化过程的基本机械洞察。最终，这项研究将为生物催化剂的性质提供洞察力，并导致新型合成催化剂的出现，这些合成催化剂结合了对金属酶反应特性的精细控制。

DESCRIPTION (provided by applicant): The broad purpose of the research in this proposal is to determine the fundamental relationships between the structures of active sites in metalloproteins and function. A bio-inspired synthetic approach is utilized that incorporates structural components found in active sites, specifically those that control the microenvironment (secondary coordination sphere) surrounding metal ion(s). Organic compounds are being developed which create rigid structures around a bound metal ion, forming specific microenvironments that emulate motifs found within protein active sites. Regulation is achieved via non- covalent interactions (e.g., hydrogen bonds) that are strategically placed proximal to the metal ions to affect function; in particular the binding and activation of dioxygen, which are processes directly linked to the maintenance of human health and aging. These synthetic systems allow for the stabilization of high-energy transients that are often proposed, but rarely observed, in non-heme metalloenzymes: their detection provides new avenues to explore mechanistic aspects of these biological essential reactions. Long-term goals include developing structure function relationships in metal-assisted oxidative catalysis. Metalloproteins perform functions not yet achieved in synthetic systems. Our hypothesis is that the lack of control of the secondary coordination sphere in synthetic compounds is a major obstacle to desired functions. Results from structural biology show that non-covalent interactions within the secondary coordination spheres of metalloproteins are instrumental in regulating function. Therefore the function and dysfunction of health-related metalloproteins can be understood in the context of changes in their microenvironments. It is still unclear, even in biomolecules, how non-covalent interactions are able to influence metal-mediated processes. Investigations into these effects require basic reactivity and mechanistic studies in which the effects of single components can be analyzed individually. We have developed synthetic systems whereby site-specific modulations in structure can be readily accomplished, in order to establish correlations with function, these types of studies will lead to fundamental mechanistic insights into biochemical processes. Ultimately, this research will provide insights into the properties of biological catalysts and lead to new classes of synthetic catalysts that incorporate the exquisite control of reactivity characteristic of metalloenzymes.