Mechanism of the proton transport in bacteriorhodopsin The intramolecular proton transfer in bacteriorhodopsin will be accompanied by several important structural changes during the photocyle in the protein matrix itself on the time scale in the millisecond range. The functional significance of the observed structural changes is an important aspect that we have investigated by using molecular kinematics methods. Since the exact pathway for proton transport is not known, we have used a combined QM/MM approach together with transition state search algorithms in order to decide between the different possible pathways. For the pathways under study and for bacteriorhodopsin proton transport in general, internal water molecules are crucial. We have used computer simulations to understand the function of particular water molecules (e.g., as proton transport intermediates) and to find positions inside the protein where functionally important water molecules need to be placed. The switch in the Schiff base accessibility is a key event of the photocycle ensuring the vectoriality of the transport which can be controlled either by making and breaking transfer pathways, or by varying the proton affinities of the binding sites. Involvement of internal water molecules in the switch is very probable and our above studies on the isomerization and proton transport also contributed to the understanding of the switch mechanism in retinal proteins [Bondar et al. Phase Transitions 77, 47-52 (2004); Bondar et al. Structure 12, 1281-1288 (2004); Bondar et al. J. Am. Chem. Soc. 126, 14668-14677 (2004); Bondar et al. Phase Transitions 78, 5-9 (2005)].
Changes in DNA methylation patterns play an important role in tumorigenesis. The DNA methyltransferase 1 (DNMT1) is a prominent target for experimental cancer therapies. However, there are only a few available inhibitors and their high toxicity and low specificity have so far precluded their broad use in chemotherapy. Based on the strong conservation of catalytic DNA methyltransferase domains we have used a homology modeling approach to determine the three-dimensional structure of the DNMT1 catalytic domain. Our results suggest an overall structural conservation with other DNA methyltransferases but also indicate local conformational differences. To test the validity of our model we used it as a template to design a novel derivative of the known DNA methyltransferase inhibitor 5-azacytidine. The resulting compound (N4-fluoroacetyl-5-azacytidine) functioned as an efficient inhibitor of DNA methylation in human tumor cell lines and also provides novel opportunities for pharmacological applications [Siedlecki et al. Biochem. and Biophys. Res. Commun. 306, 558-563 (2003); Brueckner et al. Cancer Res. 65, 6305-6311 (2005); Siedlecki et al. J. Med. Chem. 49, 678-683 (2006)]
International Max Planck Research School at the Ruprecht-Karls-Universität Heidelberg(IMPRS): Quantum Dynamics in Physics, Chemistry and Biology In recent years, quantum mechanics has shown to be of vital importance in a very broad context. Quite complex systems such as Bose-Einstein condensates, large molecules, clusters and even biological systems have been demonstrated to be governed notably by the laws of quantum mechanics. The partial control of complex quantum dynamics may lead to major applications in chemistry and biology and potentially even in medicine. Advances in mesoscopic quantum information processing may provide significant steps towards the realization of quantum computers with unprecedented efficiency.
At the German Cancer Research Centre, quantum coherence and nuclear spin play a key role in experiments which explore the dynamics and interaction of biomolecules of low mass in living tissue. Quantum chemical computations will be employed to understand the absorption of light for retinal proteins and with this the isomerization of the chromophore. Simulations of the whole protein are envisaged using combined quantum and molecular mechanics (QM/MM). We aim to provide structural information on intermediates in the photocycle and to provide a detailed picture of the complex retinal photoreaction. Furthermore, various quantum models are to be developed to study blue light photo sensors, hemi-thiolate and nucleotide binding enzymes. Particular interest will be placed on revealing the underlying mechanisms.