SFB 749: Dynamics and Intermediates of Molecular Transformations
Biology
Physics
Final Report Abstract
Chemical reactions are processes, by which substances are interconverted into others. Such transformations of matter are the basis of all life on earth. They are also used by chemical industry for the production of new materials, which do not exist in nature. Examples are the many plastic products without which our modern civilization would not be thinkable any more. Dyes and pharmaceuticals are further substances, which typically do not exist in nature and are produced by chemists through transformation of matter. Matter transformation requires the breaking and formation of new bonds between atoms. About fifteen years ago the details of such transformations which proceed on short time scales were to a large extent not understood. It was only known was many reactions proceed very fast. With the help of the newly developed femtosecond spectroscopy, which just became available at the beginning of the CRC, chemists followed ultrafast processes in real time. In the last 15 years these new methods were used in the CRC 749 to obtain fundamentally new insights how molecules react with each other and look at bond forming and bond breaking reactions in real time. A first central topic of the CRC was the question of how light is involved in such transformation processes. It was known for example that DNA of all organisms exposed to UV light undergoes specific DNA lesions. These lesions are responsible for mutagenesis processes, particularly in skin cells, which finally lead to the formation of skin cancer. It is interesting that these lesions, formed by UV light, are also repaired by light, however, by light of longer wavelength. This is achieved by the enzyme DNA photolyase, which is recognizing lesions and repairs them with the help of blue light. Within the CRC the investigation of these light-dependent repair processes was one of the initial topics. With the help of femtosecond spectroscopy, we were able to decipher the mechanism of repair, particularly the steps involved in lesion formation and lesion repair. In world-wide leading research we were finally able to analyze the reaction mechanisms in the time domain. We also overexpressed the repair proteins and were able to obtain crystal structures of the proteins in complex with DNA containing lesions. Fundamentally new insights into electron transfer reactions were gained that involved co-factors and amino acids side chains. Theoretical calculations finally allowed a full modulation of the repair reaction. This research devoted to investigate light-dependent processes was subsequently extended in the CRC 749 by the recruitment of Prof. Dr. D. Trauner from Berkeley. The research culminated finally in the development of new light triggered switches of biomolecular processes and subsequently even in the development of new light-driven molecular motors. Also in the area of metal organic chemistry, which is of central importance for the development of new substances, we were able to obtain new mechanistic insights with the help of time-resolved studies. We investigated in particular the reaction mechanisms of magnesium and zinc organic compounds. With the help of the new insights the CRC was able to develop totally new reagents (Turbo Grignard), which allow the highly selective functionalization of heterocyclic compounds. Due to the availability of these new reagents these compounds can be achieved with fewer energy and reduction of waste material. New more efficient reagents and catalysts were developed, which allow chemical transformations with fewer energy consumption. By developing new mechanistic concepts it was possible to investigate in detail the reactivity and selectivity of ambident nucleophiles, which are reactive species that have different reactivity at both ends. A major result of the CRC 749 is that the concept of hard and soft nucleophiles for rationalizing ambident reactivity has to be abandoned. It may be replaced by concepts that differentiate kinetic and thermodynamic control and consider the role of Marcus intrinsic barriers. The CRC 749 has contributed tremendously to the ability of chemists to predict organic reactivity and these results now lead to changes in standard chemistry textbooks. Predicting organic reactivity saves chemists time and synthesis energy. It reduces the amount of waste material by exploiting higher reaction efficiencies.
Publications
- Nature 2007, 450, 705. “Visualizing single molecule diffusion in mesoporous materials“
Zürner A., Kirstein J., Döblinger M., Bräuchle C., Bein T.
(See online at https://doi.org/10.1038/nature06398) - Proc. Natl. Acad. Sci. USA 2007, 104 (40), 15729-15734. “Light triggered β-hairpin folding and unfolding”
T. E. Schrader, W. J. Schreier, T. Cordes, F. O. Koller, G. Babitzki, R. Denschlag, C. Renner, S.-L. Dong, M. Löweneck, L. Moroder, P. Tavan, and W. Zinth
(See online at https://doi.org/10.1073/pnas.0707322104) - Angew. Chem. Int. Ed. 2008, 47, 10076-10080. “Crystal Structure and Mechanism of a DNA (6-4) Photolyase”
M. J. Maul, T. R. M. Barends, A. F. Glas, M. J. Cryle, T. Domratcheva, S. Schneider, I. Schlichting, T. Carell
(See online at https://doi.org/10.1002/anie.200804268) - PNAS 2009, 106 (28),11548-11553. “The archaeal cofactor F0 is a light-harvesting antenna chromophore in eukaryotes”
Glas, A. F., Maul, M. J., Cryle, M. J., Barends, T. R. M., Schneider, S., Kaya, E., Schlichting, I., Carell, T.
(See online at https://doi.org/10.1073/pnas.0812665106) - Angew. Chem. Int. Ed. 2010, 49, 4734-4737. "A Programmable DNA-Based Molecular Valve for Colloidal Mesoporous Silica"
A. Schlossbauer, S. Warncke, P. E. Gramlich, J. Kecht, A. Manetto, T. Carell, T. Bein
(See online at https://doi.org/10.1002/anie.201000827) - Chem. Phys. Lett. 2010, 498, 230-234. “First-principles study of photoinduced electron-transfer dynamics in a Mg-porphyrin-quinone complex”
R. Borrelli and W. Domcke
(See online at https://doi.org/10.1016/j.cplett.2010.08.072) - J. Am. Chem. Soc. 2010, 132, 6032-6040. “Oxidation State, Aggregation, and Heterolytic Dissociation of Allyl Indium Reagents”
K. Koszinowski
(See online at https://doi.org/10.1021/ja908101j) - J. Am. Chem. Soc. 2010, 132, 6964-6972. “Showdomycin as a versatile chemical tool for the detection of pathogenesis associated enzymes in bacteria”
Böttcher, T.; Sieber, S. A.
(See online at https://doi.org/10.1021/ja909150y) - Nature Nanotechnology 2010, 5, 271-274. “Visualization of the Self Assembly of Silica Nanochannels reveals growth mechanism”
C. Jung, P. Schwaderer, M. Dethlefsen, R. Köhn, J. Michaelis and C. Bräuchle
(See online at https://doi.org/10.1038/nnano.2010.258) - Proc. Natl. Acad. Sci. USA 2010, 107 (11), 4955-4960. “An unlocking/relocking barrier in conformational fluctuations of villin headpiece subdomain”
Reiner, A., Henklein, P. & Kiefhaber, T.
(See online at https://doi.org/10.1073/pnas.0910001107) - J. Am. Chem. Soc. 2011, 133, 6484. “Liquid-Phase Calcination of Colloidal Mesoporous Silica Nanoparticles in High-Boiling Solvents”
V. Cauda, C. Argyo, D. G. Piercey, T. Bein
(See online at https://doi.org/10.1021/ja1067492) - Angew. Chem. 2012, 124, 10064-10068; Angew. Chem. Int. Ed. 2012, 51, 9926-9930. “InCl3-katalysierte Synthese von 1,2-dimetallierten Verbindungen durch direkte Insertion von Aluminium- oder Zinkpulver“, “InCl3-Catalyzed Synthesis of 1,2-Dimetallic Compounds by Direct Insertion of Aluminum or Zinc Powder“
T. D. Blümke, T. Klatt, K. Koszinowski, P. Knochel
(See online at https://doi.org/10.1002/ange.201205169 https://doi.org/10.1002/anie.201205169) - Proc. Natl. Acad. Sci. USA 2013, 110, 12905-12910. “Testing the diffusing boundary model for the helix–coil transition in peptides”
Neumaier, S., Reiner, A., Büttner, M., Fierz, B. & Kiefhaber, T.
(See online at https://doi.org/10.1073/pnas.1303515110) - Angew. Chem. Int. Ed. 2014, 53, 591-594. “Photostability of 4,4'-Dihydroxythioindigo a mimetic of indigo”
M. Dittmann, F. F. Graupner, B. März, S. Oesterling, R. de Vivie-Riedle, W. Zinth, M. Engelhard, and W. Lüttke
(See online at https://doi.org/10.1002/anie.201307016) - J. Am. Chem. Soc. 2012, 134, 13902–13911. “Free Energy Relationships for Reactions of Substituted Benzhydrylium Ions: From Enthalpy- over Entropy- to Diffusion-Control”
J. Ammer, C. Nolte, H. Mayr
(See online at https://doi.org/10.1021/ja306522b) - Nat. Chem. Biol. 2014, 10, 574-581. “Tet oxidizes thymine to 5-hydroxymethyluracil in mouse embryonic stem cell DNA”
T. Pfaffeneder, et. al.
(See online at https://doi.org/10.1038/nchembio.1532) - PNAS 2014,111 (12), 4369-437. “Charge separation and charge delocalization identified in long-living states of photoexcited DNA”
D. B. Bucher, B. M. Pilles, T. Carell, W. Zinth
(See online at https://doi.org/10.1073/pnas.1323700111) - Angew. Chem. Int. Ed. 2015, 54, 2754-2757. “Stereoselective Synthesis and Reactions of Secondary Alkyllithium Reagents Functionalized at the 3‐Position”
K. Moriya, D. Didier, M. Simon, J. M. Hammann, G. Berionni, K. Karaghiosoff, H. Zipse, H. Mayr, P. Knochel
(See online at https://doi.org/10.1002/anie.201409165) - J. Am. Chem. Soc. 2015, 137, 9824, “Unraveling the base excision repair mechanism of human DNA glycosylase”
K. Sadeghian, C. Ochsenfeld
(See online at https://doi.org/10.1021/jacs.5b01449) - Nature Chemistry 2015, 7, 879-882. “An Eight-Step Synthesis of Epicolactone Reveals its Biosynthetic Origin”
Ellerbrock, P.; Armanino, N.; Ilg. M. K.; Webster, R.; Trauner, D.
(See online at https://doi.org/10.1038/nchem.2336) - Acc. Chem. Res. 2016, 49, 952–965, doi: 10.1021/acs.accounts.6b00071. “Philicities, Fugalities, and Equilibrium Constants“
H. Mayr, A. R. Ofial
(See online at https://doi.org/10.1021/acs.accounts.6b00071) - Angew. Chem. Int. Ed. 2016, 14, 14852-14857. “Natural product inspired amino-epoxybenzoquinones kill members of the gram-negative pathogen Salmonella by attenuating cellular stress response”
Mandl, F.A., Kirsch, V.C., Ugur, I., Kunold, E., Vomacka, J., Fetzer, C., Schneider, S., Richter, K., Fuchs, T.M., Antes, I., Sieber, S. A.
(See online at https://doi.org/10.1002/anie.201607338) - Angew. Chem. Int. Ed. 2016, 55, 9763–9767. “Rapid Access to Orthogonally Functionalized Naphthalenes: Application to the Total Synthesis of the Anticancer Agent Chartarin”
T. A. Unzner, A. Grossmann, T. Magauer
(See online at https://doi.org/10.1002/anie.201605071) - Scientific Rep. 2017, 7, 41324/1-11. “Both DNA global deformation and repair enzyme contacts mediate flipping of thymine dimer damage”
A. Knips, M. Zacharias
(See online at https://doi.org/10.1038/srep41324) - Angew. Chem. Int. Ed. 2018, 57, 10748-10751. “Sodiation of Arenes and Heteroarenes in Continuous Flow”
Weidmann, N., Ketels, M., Knochel, P.
(See online at https://doi.org/10.1002/anie.201803961) - Angew. Chem. Int. Ed. 2018, 57, 6701-6704. “Generation of Aryl and Heteroaryl Magnesium Reagents in Toluene by Br/Mg or Cl/Mg Exchange”
Ziegler, D. S., Karaghiosoff, K., Knochel, P.
(See online at https://doi.org/10.1002/anie.201802123) - J. Am. Chem. Soc. 2018, 140, 11474–11486. “Kinetics of Electrophilic Fluorinations of Enamines and Carbanions: Comparison of the Fluorinating Power of N-F Reagents“
D. S. Timofeeva, A. R. Ofial, H. Mayr
(See online at https://doi.org/10.1021/jacs.8b07147) - J. Am. Chem. Soc. 2018, 140, 5311-5318. “Complete Mechanism of Hemithioindigo Motor Rotation”
Wilcken, R., Schildhauer, M., Rott, F., Huber, L. A., Guentner, M., Thumser, S., Hoffmann, K., Oesterling, S., de Vivie-Riedle, R., Riedle, E., Dube, H.
(See online at https://doi.org/10.1021/jacs.8b02349) - J. Am. Chem. Soc. 2018, 140, 5311-5318. “Complete Mechanism of Hemithioindigo Motor Rotation”
R. Wilcken, M. Schildhauer, F. Rott, L. A. Huber, M. Guentner, S. Thumser, K. Hoffmann, S. Oesterling, R. de Vivie-Riedle, E. Riedle, and H. Dube
(See online at https://doi.org/10.1021/jacs.8b02349) - J. Am. Chem. Soc. 2018, 140, 8714-8720. “RNA Environment is Responsible for Decreased Photostability of Uracil”
S. Reiter, D. Keefer, and R. de Vivie-Riedle
(See online at https://doi.org/10.1021/jacs.8b02962) - Nat. Chem. Biol. 2018, 14, 72–78. “5-Formylcytosine to cytosine conversion by C-C bond cleavage in vivo”
K. Iwan, R. Rahimoff, A. Kirchner, F. Spada, A.S. Schröder, O. Kosmatchev, S. Ferizaj, J. Steinbacher, E. Parsa, M. Müller, T. Carell
(See online at https://doi.org/10.1038/nchembio.2531) - Nat. Commun. 2018, 9 (1168), 1-8. “Catalytic Mechanism and Molecular Engineering of Quinolone Biosynthesis in Dioxygenase AsqJ”
Mader S. L., Bräuer A., Groll M. and Kaila V. R.
(See online at https://doi.org/10.1038/s41467-018-03442-2) - Nat. Commun. 2018, 9, 2510. “Direct evidence for hula twist and single-bond rotation photoproducts”
Gerwien, A., Schildhauer, M., Thumser, S., Mayer, P. Dube, H.
(See online at https://doi.org/10.1038/s41467-018-04928-9) - Angew. Chem. Int. Ed. 2019, 58, 5758-5762. “Assessment of a large enzyme-drug complex by proton-detected solid-state NMR without deuteration“
S. K. Vasa, H. Singh, K. Grohe, R. Linser
(See online at https://doi.org/10.1002/anie.201811714) - Angew. Chem. Int. Ed. 2019, 58, 5967-5972. “Atomic resolution insight on Sac7d protein binding to DNA and associated global changes by Molecular Dynamics Simulations”
M. Zacharias
(See online at https://doi.org/10.1002/anie.201900935) - Nature Chem. Biol. 2019, 15, 623-631. “Optical Control of Sphingosine-1-Phosphate Formation and Function”
Morstein, J.; Hill, R. Z.; Novak, A. J. E.; Feng, S.; Norman, D. D.; Donthamsetti, P. C. M.; Frank, J. A.; Harayama, T.; Williams, B. M.; Parrill, A. L.; Tigyi, G. J.; Riezman, H.; Isacoff, E. Y.; Bautista, D. M.; Trauner, D.
(See online at https://doi.org/10.1038/s41589-019-0269-7)
