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

迈阿密大学的Rajeev Prabhakar得到了化学系化学催化项目的一个奖项的支持，以开发用于水解的生物启发催化剂。 生物大分子的磷酸酯和肽酰胺键的选择性水解在许多关键应用中是必需的，例如DNA修复、蛋白质工程、基因组学和治疗学。在自然界中，这些极其稳定的键被高度专业化的酶水解。然而，目前只有少数天然酶已成功地用于上述应用，但存在一些缺陷。因此，开发能够模拟天然酶活性的小分子是令人感兴趣的。然而，这一目标的实现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设计用于此类水解反应的高效和特异性催化剂。此外，Prabhakar博士积极参与为高中至本科阶段的少数群体成员提供教育和研究机会。这些外联活动包括迈阿密戴德县公立学校的荣誉和执行实习计划（HEIP），美国化学学会（ACS）的项目种子（夏季经验的经济困难）和夏季讲习班称为CATCH-计算和理论化学高中和高中研究杂志（HRJ）。本科生将通过专业课程，暑期研究计划和NSF的支持提供研究机会。 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生物启发金属基催化剂。该项目中开发的催化剂预计将是稳健和可调的。这一目标需要深入了解控制天然酶及其现有合成类似物活性的不同化学因子的作用。在这个提议中，几个国家的最先进的理论和计算化学技术，涉及分子动力学，量子力学（QM）和混合量子力学/分子力学（QM/MM）与广泛的实验相结合，以设计下一代催化剂。为了支持该项目的更广泛影响，Prabhakar博士积极培训和吸引来自社会经济和教育弱势家庭的研究生、本科生和高中的当代和后代学生。该奖项反映了NSF的法定使命，并通过使用基金会的智力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.