HYDROGEN BONDING CAVITY MOTIFS ABOUT METAL IONS

描述（由申请人提供）：本提案中研究的广泛目的是确定金属蛋白活性位点结构与功能之间的基本关系。利用生物启发的合成方法，其结合了在活性位点中发现的结构组分，特别是控制金属离子周围的微环境（次级配位层）的那些。正在开发的有机化合物可以在结合的金属离子周围产生刚性结构，形成模拟蛋白质活性位点内发现的基序的特定微环境。调节通过非共价相互作用（例如，氢键），其策略性地靠近金属离子放置以影响功能;特别是分子氧的结合和活化，这是与维持人类健康和衰老直接相关的过程。这些合成系统允许稳定的高能量瞬变，经常提出，但很少观察到，在非血红素金属酶：他们的检测提供了新的途径，探索这些生物基本反应的机制方面。长期目标包括发展金属辅助氧化催化的结构功能关系。金属蛋白质具有在合成系统中尚未实现的功能。我们的假设是，在合成化合物中缺乏对次级配位球的控制是实现所需功能的主要障碍。结构生物学的结果表明，金属蛋白的二级配位球内的非共价相互作用有助于调节功能。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理解。即使在生物分子中，非共价相互作用如何影响金属介导的过程仍然不清楚。对这些影响的调查需要基本的反应性和机制研究，其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，从而可以很容易地完成结构中的位点特异性调制，以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理的见解。最终，这项研究将提供深入了解生物催化剂的性质，并导致新的合成催化剂类别，包括金属酶的反应特性的精致控制。

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.