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

在化学系生命过程化学项目和刺激竞争研究既定项目（EPSCoR）的支持下，阿拉巴马大学伯明翰分校的Gayan B. Wijeratne博士将研究具有血红素铁中心的小分子的化学性质，例如那些在人类生物学中激活氧气的分子。这些模型系统可以是非常通用的，但对于理解控制生物中氧介导反应的复杂机制细节来说是直接的探针。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，这些知识可以引导复杂分子的有效合成途径，并发现可以提高氧还原催化剂效率的催化剂，从而有利于替代能源的应用。这项工作将涉及生物灵感的设计和结合有机和无机合成工具包的新模型系统的合成，以及与生物功能相似的反应性分析。此外，将采用各种各样的低温光谱工具，为贡献高中，本科生，研究生和博士后研究人员提供独特的专业技能。该项目的推广和教育方面将包括通过新设计的科学俱乐部项目向伯明翰市高中学生介绍区域科学博览会。拟议的努力将努力弥合伯明翰市青少年科学素养的差距，伯明翰市是全国收入隔离最严重的学区之一。含血红素双加氧酶在人体生理、疾病进展和衰老中起着关键作用，因此在过去十年中引起了大量的研究兴趣。然而，关于这些的确切的机械细节只是模糊的理解。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，有关它们在实际酶促机制中的确切参与的细节仍然难以捉摸。长期以来，合成模型系统一直是解决这种机制模糊性的有力工具，但合成血红素超氧化物加合物经常被发现是迟钝的氧化剂。这种异常要求对合成系统的显式建模进行重新评估，与它们的生物作用模式直接相关。对这种模型系统的机理细节的理解也可以直接有利于设计针对重要的复杂有机分子和均相双氧还原催化剂的高级合成方法，以用于替代能源应用。拟议的研究将通过生成具有不同结构性质的合成血红素超氧化物模型系统库，并深入研究这种结构调节如何影响其反应性特征，来解决这一知识空白。这项工作将垂直推进对中间价血红素-氧中间体的反应性控制几何、电子和非共价结构性质的基本理解，引入血红素-氧模型化学的新时代。该项目的推广活动将通过前沿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性不足的高中生，旨在加强他们为区域科学博览会做准备的阶段。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.