Invited Lecture – Walter Thiel

In recent years, it has become possible to model chemical reactions in large biomolecules using combined quantum mechanical / molecular mechanical (QM/MM) methods. After a general outline of the theoretical background and the chosen strategy,^[1,2] the lecture will describe some of our recent work on biocatalysis by enzymes, in particular cytochrome P450cam.^[3-8] Topics include the electronic structure of P450cam intermediates, two-state reactivity in the oxygenation reaction, the biocatalytic role of single water molecules, revised mechanisms for the formation of the Compound I intermediate, and the competition between coupling and uncoupling reactions in the wild-type enzyme and several mutants. P450cam will thus serve as an example of the chemical insights and the improved mechanistic understanding that can be provided by QM/MM calculations. Time permitting, the lecture will also address theoretical studies that rationalize the improved enantioselectivity of lipase mutants generated by directed evolution in our institute.^[9]

1. H. M. Senn, W. Thiel, Top. Curr. Chem. 2007, 268, 173-290.
2. H. M. Senn, W. Thiel, Angew. Chem. Int. Ed. 2009, 48, 1198-1229. 
3. J. C. Schöneboom, H. Lin, S. Cohen, S. Shaik, W. Thiel, J. Am. Chem. Soc. 2004, 126, 4017-4034. 
4. J. C. Schöneboom, F. Neese, W. Thiel, J. Am. Chem. Soc. 2005, 127, 5840-5853. 
5. J. Zheng, D. Wang, W. Thiel, S. Shaik, J. Am. Chem. Soc. 2006, 127, 13204-13215. 
6. A. Altun, S. Shaik, W. Thiel, J. Am. Chem. Soc. 2007, 129, 8978-8987. 
7. D. Wang, J. Zheng, S. Shaik, W. Thiel, J. Phys. Chem. B 2008, 112, 5126-5138
8. M. Altarsha, T. Benighaus, D. Kumar, W. Thiel, J. Am. Chem. Soc. 2009, 131, 4755-4763. 
9. M. T. Reetz, M. Puls, J. D. Carballeira, A. Vogel, K.-E. Jaeger, T. Eggert, W. Thiel, M. Bocola, N. Otte, ChemBioChem 2007, 8, 106-112.