Development of Bio-Inspired Synthetic Metallopeptidases: Insight from Theoretical Studies

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With this award from the Chemical Catalysis Program of the Chemistry Division, Professor Rajeev Prabhakar from the University of Miami will utilize theoretical and computational chemistry techniques to derive guiding principles of peptide hydrolysis and apply them for the development of efficient bio-inspired synthetic metallopeptidases. The selective hydrolysis of the extremely stable peptide or amide bond (-(O=)C-NH-) of peptides and proteins plays a critical role in a wide range of biological, biotechnological and industrial applications. A wealth of experimental data indicates that remarkable changes in catalytic efficiency can be attained in peptide hydrolysis with modifications in the metal ions or the ligands (direct and indirect) of the metal centers. The approach is to first understand the roles of metal(s) and ligands of mono- and binuclear metal center containing enzymes and their existing synthetic analogues in their functioning. This knowledge will then be used to modify metal(s) and ligands and rigorously integrated with experiments performed by our collaborators to design the next generation of efficient synthetic metallopeptidases. These analogues can offer the following advantages over natural enzymes and synthetic reagents: (1) they are inexpensive and may be recyclable, (2) being smaller in size they impose little or no steric constraints, (3) they can cleave proteins either terminally or internally, and (4) their properties can be tuned for specific applications such as protein engineering, proteomics and therapeutics. The calculations will also validate the applicability of different density functional theory (DFT) functionals, force field parameters, hybrid quantum mechanics(QM) and molecular mechanics (MM) such as QM/MM and QM/QM/MM methods and mechanical and electronic embedding schemes on the transition metal containing complexes. The potential advantages to society offered by the synthetic metallopeptidases developed in this project include energy, water and raw material conservation and therapeutics, which are critical to energy reliance, environmental protection and health. This project also has a significant broader impact in terms of training and involving current and future generations of students at the graduate, undergraduate and high school levels throughout the year. In particular, it will engage talented students from socio-economic and educationally disadvantaged families to advance research in theoretical chemistry. The high school students will be engaged in research through 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 to be designed by the PI called CATCH-Computational and Theoretical Chemistry for High School. The undergraduate students will be provided research opportunities through NSF support and two specialized courses and a summer research program offered in the department.