Understanding and Controlling the Selectivity of Visible Light Photocatalysis in Metal Polypyridyl Artificial Metalloenzymes

在化学系化学催化项目的支持下，Jared C.印第安纳州大学的刘易斯正在研究一类新的人工金属酶（ArMs），这种酶有望通过在选择性和功能上比现有技术有重大改进来推进生物酶领域的发展。所提出的ArMs将使用可见光来实现广泛的具有挑战性的化学反应的合成催化剂纳入蛋白质支架中，从而能够对这些反应的过程进行空间控制。因此，所设计的ArM构建体将提供独特的平台来控制反应的选择性，所述反应可用于化学合成并且可能适用于药物、农用化学品和其他先进材料的制造。资助项目的更广泛影响将扩展到一个综合推广计划，重点是通过创新的教育内容模块提高研究生，本科生和高中生对生物催化重要主题的理解。为了补充这一活动，将开发一个高中教师专业发展计划，同样探讨生物催化的主题。了解酶如何可以作为不同的催化反应的主机，以及第二球相互作用和构象动力学如何影响金属辅因子的性质和反应性，将大大提高我们使用蛋白质作为超分子催化主机的能力。此外，从这些努力中获得的见解将阐明在催化中更广泛地实施第二球体相互作用的设计原则。刘易斯小组的先前研究导致了基于脯氨酰寡肽酶（POP）支架的ArMs的开发，并且鉴定了进化这些ArMs的稳健方法。这项工作揭示了有吸引力的相互作用和构象动力学影响与POP连接的金属络合物的辅因子结合/生物缀合、催化选择性和生物物理性质。资助的项目进一步发展了这些想法，并将专注于开发一类新的基于POP的金属聚吡啶ArMs，同时需要努力：（a）理解金属多吡啶结合和POP内的电子物理性质，（B）开发用于选择性光氧化还原和能量转移催化的共价金属多吡啶ArMs，和（c）设计非共价ARM以控制市售光催化剂的选择性。计划中的研究旨在阐明构象动态蛋白质支架中的非共价相互作用如何调节辅因子反应性。这种方法将补充生物无机化学中的努力，以模拟金属辅因子与静态合成辅因子类似物或静态蛋白质支架对金属离子反应性的影响。使用所提出的ArMs来控制宽范围的光氧化还原性质的选择性的潜力也具有显著影响合成方法的潜力。该奖项反映了NSF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 the support of the Chemical Catalysis Program in the Division of Chemistry, Jared C. Lewis of Indiana University is studying a new class of artificial metalloenzymes (ArMs) that promise to advance the field of photocatalysis by offering significant improvements in selectivity and function over existing technologies. The proposed ArMs incorporate synthetic catalysts that use visible light to effect a broad range of challenging chemical reactions, into protein scaffolds that will enable spatial control over the course of these reactions. As such, the designed ArM constructs will provide a unique platform to control the selectivity of reactions that are useful for chemical synthesis and potentially applicable for the manufacture of pharmaceuticals, agrochemicals, and other advanced materials. The broader impacts of the funded project will extend to an integrated outreach program focused on improving understanding of the important topic of biocatalysis among graduate, undergraduate, and high school students via innovative educational content modules. To complement this activity, a high school teacher professional development program will be developed that likewise explores the theme of biocatalysis.Understanding how enzymes can serve as hosts for different catalytic reactions and how second sphere interactions and conformational dynamics influence the properties and reactivity of metal cofactors, would greatly improve our ability to use proteins as supramolecular hosts for catalysis. Furthermore, the insights gained from such endeavors will shed light on design principles for implementing second sphere interactions more broadly in catalysis. Previous studies in the Lewis group led to the development of ArMs based on a prolyl oligopeptidase (POP) scaffold and robust methods to evolve these ArMs were identified. The work revealed that attractive interactions and conformational dynamics impact cofactor binding/bioconjugation, catalytic selectivity, and photophysical properties of metal complexes linked to POP. The funded project takes these ideas further and it will focus on the development of a new class of POP-based metal polypyridine ArMs while entailing efforts to: (a) understand metal polypyridine binding and photophysical properties within POP, (b) evolve covalent metal polypyridine ArMs for selective photoredox and energy transfer catalysis, and (c) engineer non-covalent ArMs to control the selectivity of commercially available photocatalysts. The planned research aims to illuminate on how non-covalent interactions in a conformationally dynamic protein scaffold can modulate cofactor reactivity. This approach will complement efforts in bioinorganic chemistry to model metallocofactors with static synthetic cofactor analogues or the effects of static protein scaffolds on metal ion reactivity. The potential to control the selectivity of a broad range of photoredox properties using the proposed ArMs also has the potential to significantly impact synthetic methodology. These studies will provide an ideal backdrop for improving understanding of biocatalysis at multiple levels.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.