CAREER: Geometric and Electronic Contributions to Bio-inspired Reactivities of Heme-superoxide Intermediates

阿拉巴马大学伯明翰分校的Gayan B.WiJeratne博士将在化学系生命过程化学计划和已建立的刺激竞争研究计划(EPSCoR)的支持下，研究具有血红素铁中心的小分子的化学，例如那些在人类生物学中激活氧的中心。这些模型系统可以是非常通用的，但直接的探测器，以了解复杂的机制细节，管理氧在生物学中的反应。WiJeratne博士和他的团队将利用这些强大的工具来揭示未知的知识，这些知识可能导致有效合成复杂分子的途径，以及可以提高氧还原催化剂的效率的催化剂的发现，这些催化剂有利于替代能源的应用。这项工作将涉及以生物为灵感设计和合成结合有机和无机合成工具包的新模型系统，以及分析与生物功能相似的反应性。此外，还将使用各种低温光谱分析工具，为高中、本科生、研究生和博士后研究人员提供独特的专业技能。该项目的外展和教育方面将包括伯明翰高中生通过新设计的科学俱乐部计划向地区科学博览会定向。拟议中的努力将努力缩小伯明翰市年轻人的科学素养差距，伯明翰是英国收入差距最大的学区之一。含血红素的双加氧酶在人类生理、疾病进展和衰老中起着关键作用，因此在过去的十年里吸引了大量的研究兴趣。然而，关于这些的确切的机械细节只被模糊地理解。血红素超氧化物加合物被认为是血红素双加氧酶中的活性氧化剂，然而，关于它们在实际酶机制中的确切参与细节仍然难以捉摸。合成模型系统长期以来一直是解决这种机制模糊性的强大工具，但合成的血红素超氧化物加合物经常被发现是迟缓的氧化剂。这种反常现象要求对与生物作用模式直接相关的合成系统的显式建模进行重新评估。对这些模型体系的机理细节的理解也可以直接有益于针对重要的复杂有机分子和用于替代能源应用的均相氧还原催化剂的优秀合成方法的设计。拟议的研究将通过建立具有不同结构属性的合成血红素超氧化物模型体系库来解决这一知识缺口，并彻底调查这种结构调节将如何影响其反应性特征。这项工作将纵向推进对中价血红素-氧中间体的反应性控制的几何、电子和非共价结构性质的基本理解，引入血红素-氧模型化学的新纪元。该项目的外展活动将通过尖端研究机会和高质量的一对一指导机会，直接惠及阿拉巴马州伯明翰地区大多数代表不足的高中生，旨在加强他们为地区科学博览会的筹备阶段。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With support from the Chemistry of Life Processes Program in the Division of Chemistry and the Established Program to Stimulate Competitive Research (EPSCoR) Dr. Gayan B. Wijeratne at the University of Alabama at Birmingham will investigate the chemistry of small molecules with heme iron centers such as the ones that activate oxygen in human biology. These model systems can be extremely versatile, yet straightforward probes for comprehending the complicated mechanistic details that govern oxygen mediated reactivities in biology. Dr. Wijeratne and his team will utilize these powerful tools in shedding light on yet unknown knowledge that can lead to pathways for efficient syntheses of complex molecules, and the discovery of catalysts that can enhance the efficiency of catalysts of oxygen reduction benefiting alternative energy applications. This work will involve bio-inspired design and synthesis of fresh model systems that combine organic and inorganic synthetic toolkits, and analyses of reactivities that draw parallels to biological functionalities. As well, a broad variety of cryogenic spectroscopic tools will be employed, offering a uniquely specialized skillset to contributing high-school, undergraduate, graduate, and postdoctoral researchers. Outreach and educational aspects of this project will involve the orientation of Birmingham City high school students toward Regional Science Fair via a newly designed Science Club program. Proposed efforts will strive to bridge the gap of scientific literacy of youngsters in the City of Birmingham, which is one of the most income-segregated school districts in the country. Heme-containing dioxygenases play pivotal roles in human physiology, disease progression, and aging, consequently attracting substantial research interests within the past decade. However, exact mechanistic details concerning these are only faintly understood. Heme superoxide adducts are presumed to be active oxidants in heme dioxygenases, however, details pertaining to their definitive involvement in the actual enzymatic mechanism remain elusive. Synthetic model systems have long-served as powerful tools in addressing such mechanistic ambiguities, but synthetic heme superoxide adducts are often found to be sluggish oxidants. This anomaly calls for revaluation of explicit modeling of synthetic systems with direct relevance to their biological mode of action. Comprehension of mechanistic details of such model systems can also be of direct benefit for the design of superior synthetic methodologies targeting important complex organic molecules and homogeneous dioxygen reduction catalysts to be used in alternative energy applications. Proposed research will address this gap in knowledge by generating a library of synthetic heme superoxide model systems with divergent structural properties, and thorough investigation into how such structural modulations would influence their reactivity signatures. This work will vertically advance the fundamental understanding of reactivity-governing geometric, electronic, and non-covalent structural properties of mid-valent heme-oxygen intermediates, introducing a new era of heme-oxygen model chemistry. Outreach activities of this project will directly benefit the majority of underrepresented high schoolers in the Birmingham, Alabama area through cutting-edge research opportunities and high-quality one-on-one mentoring opportunities geared toward strengthening their preparatory phase for Regional Science Fair.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.