Mechanistic insights into C-H bond activation in mononuclear non-heme iron enzymes from a combination of experiment and quantum chemistry

• Applicant: Professor Dr. Frank Neese
• Subject Area: Theoretical Chemistry: Electronic Structure, Dynamics, Simulation
• Term: from 2007 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 49804235

Metalloenzymes play vital role in metabolism, in particular, they are capable to oxidize unactivated aliphatic C-H bonds of hydrocarbons employing the “green” oxidant dioxygen.[1,2] Understanding the catalytic mechanisms of metalloenzyme reactions at the atomic level will enhance our knowledge for further design and synthesis of novel low-molecular weight “green” catalysts. Quantum chemical approaches provide key contributions to this important field of investigation: (1) Calculation of the spectroscopic parameters of potential reaction intermediates and comparison with experimentally determined properties is vital for the structural elucidation of short lived species that are inaccessible to X-ray crystallography; (2) Optimization of the structures of transition states in order to “connect” these intermediates and to predict reaction rates and kinetic isotope effects; (3) Qualitative analysis of the electronic structures of these intermediates and transition states provides deep chemical insight into the catalytic mechanisms, (4) The combined analysis triggers new ideas for conclusive experiments that probe the intricate details of the catalytic mechanisms. This proposal is aimed at the elucidation of the catalytic mechanisms of Taurine:α- Ketoglutarate Dioxygenase (TauD), α-KG-dependent oxygenase/halogenase (SyrB2), and Isopenicillin N sythase (IPNS). All of these enzymes feature mononuclear nonheme iron centers, and were investigated in detail experimentally by our american project partners. In addition to the fruitful interaction with the experimentally oriented project partners we plan to engage in a theoretical collaboration with the Hammes- Schiffer group that is specialized in hydrogen atom transfer reactions in large molecules. This synergetic approach will enable us to understand the relationship between the electronic and geometric structure of these enzymes and their enzymatic activity in sub-atomic detail. Tasks to be completed include: 1. Calculation of spectroscopic parameters of their intermediates, verification of the results by comparison with experimental findings. 2. Location of transition states on the potential energy surfaces (PES), gaining detailed energetic information on the catalytic cycle. Particular emphasis will be laid on the important subject on spin-state energetics in relation to the concept of two-state reactivity. Analysis of electronic structure of these intermediates and transition states to understand the catalytic mechanism at the atomic level.

• DFG Programme: Research Grants
• International Connection: USA
• Participating Persons: Professor Dr. J. Martin Bollinger; Professorin Sharon Hammes-Schiffer; Professor Dr. Carsten Krebs