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

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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.