CAS: Development of Bio-inspired Catalysts for Hydrolysis: Insights from Theoretical Studies

迈阿密大学的Rajeev Prabhakar获得了化学系化学催化项目的奖励，以开发生物启发的水解催化剂。生物大分子的磷酸酯和肽酰胺键的选择性水解在DNA修复、蛋白质工程、基因组学和治疗学等许多关键应用中都是必需的。在自然界中，这些极其稳定的键被高度特化的酶水解。然而，目前只有少数天然酶成功地用于上述应用，并且存在一些不足。因此，开发能够模拟天然酶活性的小分子是人们感兴趣的。然而，实现这一目标是非常具有挑战性的，需要严格的实验和理论计算相结合。在这个项目中，Prabhakar博士将首先推导出磷酸酯、肽和羧酸酯水解的指导原则，然后将这些原则应用于此类水解反应的高效和特定催化剂的设计。此外，Prabhakar博士积极参与为高中到本科阶段的少数群体成员提供教育和研究机会。这些拓展活动包括迈阿密-戴德县公立学校的荣誉和行政实习计划（HEIP），美国化学学会（ACS）的SEED项目（经济弱势群体暑期体验）和一个名为catch的暑期研讨会——高中计算和理论化学和高中研究期刊（HRJ）。本科生将通过专业课程、暑期研究项目和国家科学基金会的支持获得研究机会。在化学部化学催化项目的资助下，迈阿密大学的Rajeev Prabhakar博士正在通过理论计算研究磷酸酯、肽和羧酸酯键的水解机理。研究结果将用于开发高效的仿生金属基催化剂。该项目开发的催化剂有望具有鲁棒性和可调性。这一目标需要对控制天然酶及其现有合成类似物活性的不同化学因素的作用有深刻的理解。本研究将分子动力学、量子力学（QM）和混合量子力学/分子力学（QM/MM）等先进的理论和计算化学技术与广泛的实验相结合，设计下一代催化剂。为了支持该项目产生更广泛的影响，普拉巴卡博士正在积极培训和吸引来自社会经济和教育条件较差家庭的研究生、本科生和高中的当代和未来几代学生。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。

Rajeev Prabhakar of the University of Miami is supported by an award from the Chemical Catalysis program in the Division of Chemistry to develop bio-inspired catalysts for hydrolysis. The selective hydrolysis of the phosphate ester, and peptide amide bonds of bio-macromolecules is required in many critical applications such as DNA repair, protein engineering, genomics and therapeutics. In nature, these extremely stable bonds are hydrolyzed by highly specialized enzymes. However, currently only a few natural enzymes have been successfully employed for the aforementioned applications but with some deficiencies. Therefore, the development of small molecules that can mimic the activities of natural enzymes is of interest. However, realization of this goal is very challenging and necessitates a rigorous integration of experiments and theoretical calculations. In this project, Dr. Prabhakar will first derive the guiding principles of phosphate ester, peptide and carboxylate ester hydrolysis and then work to apply these principals to the design of efficient and specific catalysts for such hydrolysis reactions. Additionally, Dr. Prabhakar is actively involved in providing educational and research opportunities to members of minority groups at the high school through undergraduate levels. These outreach activities include the Honors and Executive Internship Program (HEIP) of the Miami-Dade County Public Schools, the American Chemical Society's (ACS) Project SEED (Summer Experiences for the Economically Disadvantaged) and a summer workshop called CATCH-Computational and Theoretical Chemistry for High School and a High School Research Journal (HRJ). The undergraduate students will be provided research opportunities through specialized courses, a summer research program and support from the NSF. With funding from the Chemical Catalysis Program of the Chemistry Division, Dr. Rajeev Prabhakar of the University of Miami is studying the mechanism of the hydrolysis of phosphate ester, peptide and carboxylate ester bonds with theoretical calculations. The results are then to be utilized for the development of efficient bio-inspired metal-based catalysts. The catalysts developed in this project are expected to be robust and tunable. This goal requires a deep understanding of the roles of distinct chemical factors that govern the activities of both natural enzymes and their existing synthetic analogues. In this proposal several state-of-the-art theoretical and computational chemistry techniques involving molecular dynamics, quantum mechanics (QM) and hybrid quantum mechanics/molecular mechanics (QM/MM) are integrated with a wide range of experiments to design the next generation of catalysts. In support of the broader impact of the project, Dr. Prabhakar is actively training and engaging current and future generations of students at the graduate, undergraduate and high school levels from socio-economic and educationally disadvantaged families.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.