Development of Bio-inspired Synthetic Metallohydrolases Based on Theoretical Insights

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Development of Bio-inspired Synthetic Metallohydrolases Based on Theoretical Insights The breaking of chemical bonds in peptides (small proteins) and other biologically-important molecules by reaction with water is important. This reaction, known as hydrolysis, plays a critical role in a wide range of biological, biotechnological, and industrial applications. Nature has devised highly specialized enzymes known as metallohydrolases to enable these reactions. However, most of the natural enzymes work only under specific conditions. The development of efficient, environmentally-friendly, and economical molecules that mimic the natural enzymes is highly desirable. Their design and synthesis is challenging topic of research that requires interdisciplinary cooperation. In this project, Professor Prabhakar, University of Miami, is developing a fundamental understanding of hydrolysis and applying it to the design of synthetic metallohydrolases. This research links the basic chemical reactions involved in these processes to potential biological, biotechnological, and industrial applications. Dr. Prabhakar is also providing educational and research opportunities to members of minority groups at the high school and 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 Project SEED (Summer Experiences for the Economically Disadvantaged), a summer workshop (CATCH: Computational and Theoretical Chemistry for High School) and a High School Research Newsletter (HRN). Additionally, undergraduate students are conducting research through two specialized courses and a summer research program. With funding from the Chemical Catalysis Program of the Chemistry Division, Professor Rajeev Prabhakar of the University of Miami is deriving guiding principles of peptide (-(O=)C-NH-) and phosphoester ((O=)(RO)(RO)(P-O-R)) hydrolysis for the development of efficient bio-inspired synthetic metallohydrolases. These analogues are likely to offer the following advantages over natural enzymes: (1) inexpensive and recyclable, (2) smaller in size with little or no steric constraints, and (3) tunable for specific functions. However, the critical structural and mechanistic information required for their development cannot be readily obtained through existing experimental techniques. In this research, 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 experiments to first derive the guiding principles of peptide and phosphoester hydrolysis and then apply them to design inexpensive, environment friendly, efficient, specific, and catalytic analogues. These calculations are also validating the applicability of different Density Functional Theory (DFT) functionals, force field parameters, and hybrid QM/MM and QM/QM/MM methods with mechanical and electronic embedding schemes on metallohydrolases and their synthetic analogues. In support of the broader impacts 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-economically- and educationally-disadvantaged families through the Honors and Executive Internship Program (HEIP) of Miami-Dade County Public Schools, the American Chemical Society's Project SEED (Summer Experiences for the Economically Disadvantaged), a summer workshop called CATCH-Computational and Theoretical Chemistry for High School and a High School Research Newsletter (HRN). The undergraduate students are involved in research supported by the NSF and an existing summer program and specialized courses at the University of Miami.