Collaborative Research: CDS&E: Computational Investigation of Solvent Effects on Enzyme Catalysis

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Enzymes are specialized proteins that catalyze chemical reactions in biological systems. Changes in temperature, pressure, or composition of the environment surrounding the protein, among many other factors, can have significant effects on enzyme catalyzed reactions. With this award, the Chemistry of Life Processes Program of the Chemistry Division is funding Dr. G. Andres Cisneros from the University of North Texas and Dr. Pengyu Ren from the University of Texas at Austin to develop computational methods and software to accurately predict the effects that charges in the surrounding solvent have on enzymatic catalysis. Detailed understandings for how enzymes function in highly charged solvents (ionic liquids) potentially lead to the development of new bio-inspired catalysts for biotechnology and bioengineering applications. The state-of-the-art computational methods from this project are used to investigate the reaction mechanisms of horseradish peroxidase (HRP) in different charged solutions. Peroxidases are important enzymes that help prevent oxidative damage in aerobic organisms. The newly developed methods and source codes for programs are made freely available, which impact the ability of the scientific community to predict the behavior of enzymes in a variety of environments. In addition, the project engages school students and teachers from underrepresented minority groups in the sciences through various outreach and mentoring programs at the two participating institutions.The main premise of this project is that differences in temperatures at which homologous enzymes show maximum activity arise from differences in the balance between enthalpic and entropic contributions to the free energies of activation, even when these free energies are similar. This difference in enthalpic-entropic balance is due to differences in flexibility of surface residues. Alternatively, effects on the flexibility of surface residues from interactions with the solvent may exert long range-electrostatic effects on the active sites. Therefore, the main goal of this study is to apply quantum mechanics/molecular mechanics (QM/MM) simulations to investigate the effect of highly charged ionic liquid (IL) solutions on the enthalpic-entropic balance for enzymatic catalysis. This project continues the development of the AMOEBA-IL (atomic multipole optimized energetics for biomolecular applications in ionic liquids) force field and implements enhanced sampling methods in the QM/MM code of the LICHEM (Layered Interacting Chemical Models) package and its interface to TINKER-OpenMM molecular mechanics/dynamics sortware package. These tools are used to computationally model the reaction mechanism of horseradish peroxidase in different IL solutions. Arrhenius plots calculated for the various IL solution systems determine the enthalpic-entropic balance for each tested system to ascertain the effect of the different solvent environments on the reaction pathway. Results from this work provide fundamental insights into the role of solvents on enzyme catalysis and the role/impact of surface-residue flexibility on enzymatic reaction mechanisms. Additionally, this project develops new methods and parameters for AMOEBA, and these are made available to the broad scientific community.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.