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This thesis is concerned with quantum dynamical propagation methods suitable for high-dimensional systems, and their application to excitation energy transfer (EET), electron transfer (ET), and intra-molecular vibrational redistribution (IVR) in molecular aggregates. The theoretical description of these processes, which are often ultrafast – with time scales in the range of femtoseconds to picoseconds – is challenging, both with regard to quantum dynamical simulations and electronic structure calculations.
The present thesis comprises two parts. The first part concerns the implementation of a novel quantum dynamical method based on Gaussian Wavepackets (GWPs): the 2-Layer Gaussian-MCTDH (2L-GMCTDH) method. This method, which has recently been proposed in [S. Römer, M. Ruckenbauer, I. Burghardt, The Journal of Chemical Physics, 2013, 138, 064106] was implemented in a Fortran90 code and applied to various high-dimensional test systems. The second part of the thesis addresses the combined electronic structure and dynamical study of a novel type of donor-acceptor systems that have been investigated in a joint project with experimental collaboration partners at Strasbourg University. In both parts, numerical applications focus on high-dimensional model Hamiltonians for EET and ET processes.
Regarding the first part, the interest of using GWP-based methods is two-fold: First, GWPs represent spatially localized basis sets that are useful for on-the-fly dynamics in conjunction with electronic structure calculations. Second, they are naturally suited for the explicit representation of quantum mechanical system-bath type problems where a large number of vibrational bath modes are weakly perturbed from equilibrium. In this context, various methods exist that are based upon classically evolving GWP bases. A major improvement results from variational methods which involve optimized, non-classical GWP trajectories. In particular, the variational Gaussian-based Multi-Configuration Time-Dependent Hartree (GMCTDH) and its variational Multi-Configurational Gaussians (vMCG) variant were originally derived as semiclassical variants of the Multi-Configuration Time-Dependent Hartree (MCTDH) method. However, the G-MCTDH and vMCG methods mostly use Frozen Gaussian (FG) basis sets that are far less flexible than the single-particle (SPF) representation of standard MCTDH. As a consequence, a significantly larger number of GWPs are generally required to reach convergence. To remedy the lack of flexibility of the FG basis sets, the abovementioned two-layer (2L-G-MCTDH) approach has been introduced: Here, the first layer is composed of flexible SPFs, while the second layer is composed of low-dimensional FGs. The numerical scaling properties are significantly improved as compared with the conventional G-MCTDH and vMCG schemes. The first implementation of the method in an in-house Fortran90 code is presented, along with applications to (i) a model of site-to-site vibrational energy flow in the presence of intra-site vibrational energy redistribution (IVR) and (ii) a multidimensional donor-acceptor electron transfer system described within a linear vibronic coupling model. The second system relates to a model for ET at an oligothiophene-fullerene interface relevant to organic photovoltaics. Besides the description of the implementation, a detailed assessment of the convergence properties and comparison with multi-layer MCTDH (ML-MCTDH) benchmark calculations is presented. Finally, a perspective is given on the future combination with the existing ML-MCTDH scheme; indeed, such a combination is straightforward since the first layer of the 2L-G-MCTDH approach can be chosen to be orthogonal.
Regarding the second part of the thesis, two generations of a novel donor-acceptor (DA) system for organic photovoltaics applications, involving self-assembled block co-oligomers DA dyads and triads with perylene-diimide (PDI) accepter units, are addressed within a collaborative project with S. Haacke and S. Mery (University of Strasbourg). Based upon detailed excited-state electronic structure investigations along with quantum dynamical and kinetic studies, the relevant ET formation and recombination steps are characterized quantitatively, in view of optimizing the chemical design and reducing recombination losses.
In a first-generation variant of the abovementioned DA systems, which involves liquid-crystalline triads, we were able to show that a highly efficient inter-chain ET process prevails over intra-molecular ET, leading to fast recombination. Due to the latter, this system turns out to be inefficient for photovoltaic applications. To fully understand the elementary steps, high-dimensional quantum dynamics simulations were carried out using the ML-MCTDH method, in collaboration with Matthias Polkehn from our group. In the second-generation variant, which is in the focus of the present thesis, both the nanomorphology and the chemical design were modified. The present work, focuses upon the aspect of chemical design, by characterizing a series of modified DA’s, with donor units of varying length while the PDI accepter units remain unchanged. The intra-molecular ET is observed in these systems, but the processes are comparatively slow, of the order of tens to hundreds of picoseconds. Hence, a kinetic analysis using the Marcus-Levich-Jortner rate theory is employed. Among the main results of the study is that addition of an electron donating amine unit strongly increases the lifetime of the charge-separated state, and therefore reduced recombination losses.
Overall, the present thesis shows how a combination of high-dimensional quantum dynamics, electronic structure calculations, and vibronic coupling model Hamiltonians can be employed to obtain an accurate picture of EET, ET, and IVR in high-dimensional molecular assemblies. Furthermore, the 2L-GMCTDH method paves the way for accurate and efficient on-the-fly calculations; a suitable set-up for such calculations is currently in progress.
Orientation-selective DEER (Double Electron-Electron Resonance) measurements were conducted on a series of rigid and flexible molecules containing Cu(II) ions. A system with two rigidly held Cu(II) ions was afforded by the protein homo-dimer of copper amine oxidase from Arthrobacter globiformis. This system provided experimental DEER data between two Cu(II) ions with a well-defined distance and relative orientation to assess the accuracy of the methodology. Evaluation of orientation-selective DEER (os DEER) on systems with limited flexibility was probed using a series of porphyrin-based Cu(II)–nitroxide and Cu(II)–Cu(II) model systems of well-defined lengths synthesized for this project. Density functional theory was employed to generate molecular models of the conformers for each porphyrin-based Cu(II) dimer studied. Excellent agreement was found between DEER traces simulated using these computed conformers and the experimental data. The performance of different parameterised structural models in simulating the experimental DEER data was also investigated. The results of this analysis demonstrate the degree to which the DEER data define the relative orientation of the two Cu(II) ions and highlight the need to choose a parameterised model that captures the essential features of the flexibility (rotational freedom) of the system being studied.
In the title compound, C17H18N2O, the central carbon atom with the OH substituent and one of the (E)-benzylideneamino substituents are disordered over two sets of sites with occupancies of 0.851 (4) and 0.149 (4). The relative positions of the two disorder components is equivalent to a rotation of approximately 60° about the C—N single bond. In the crystal, the molecules are held together by O—H...N hydrogen bonds, forming simple C(5) chains along the b-axis direction. In addition, pairs of the chains are further aggregated by weak C—H...π interactions.
Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complex membrane protein complexes. The enzyme contributes substantially to oxidative energy-conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. Here, we report the X-ray structure of mitochondrial complex I at 3.6- 3.9 Å resolution describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the ‘deactive’ form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site rendering support for a two-state stabilization-change mechanism of protonpumping.
Although often depicted as rigid structures, proteins are highly dynamic systems, whose motions are essential to their functions. Despite this, it is difficult to investigate protein dynamics due to the rapid timescale at which they sample their conformational space, leading most NMR-determined structures to represent only an averaged snapshot of the dynamic picture. While NMR relaxation measurements can help to determine local dynamics, it is difficult to detect translational or concerted motion, and only recently have significant advances been made to make it possible to acquire a more holistic representation of the dynamics and structural landscapes of proteins. Here, we briefly revisit our most recent progress in the theory and use of exact nuclear Overhauser enhancements (eNOEs) for the calculation of structural ensembles that describe their conformational space. New developments are primarily targeted at increasing the number and improving the quality of extracted eNOE distance restraints, such that the multi-state structure calculation can be applied to proteins of higher molecular weights. We then review the implications of the exact NOE to the protein dynamics and function of cyclophilin A and the WW domain of Pin1, and finally discuss our current research and future directions.
Post-translational modification of proteins with ubiquitin-like SUMO modifiers is a tightly regulated and highly dynamic process. The SENP family of SUMO-specific isopeptidases comprises six cysteine proteases. They are instrumental in counterbalancing SUMO conjugation, but their regulation is not well understood. We demonstrate that in hypoxic cell extracts, the catalytic activity of SENP family members, in particular SENP1 and SENP3, is inhibited in a rapid and fully reversible process. Comparative mass spectrometry from normoxic and hypoxic cells defines a subset of hypoxia-induced SUMO1 targets, including SUMO ligases RanBP2 and PIAS2, glucose transporter 1, and transcriptional regulators. Among the most strongly induced targets, we identified the transcriptional co-repressor BHLHE40, which controls hypoxic gene expression programs. We provide evidence that SUMOylation of BHLHE40 is reversed by SENP1 and contributes to transcriptional repression of the metabolic master regulator gene PGC-1α. We propose a pathway that connects oxygen-controlled SENP activity to hypoxic reprogramming of metabolism.
Mammalian oocytes are arrested in the dictyate stage of meiotic prophase I for long periods of time, during which the high concentration of the p53 family member TAp63α sensitizes them to DNA damage-induced apoptosis. TAp63α is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. Here we show that the TAp63α dimer is a kinetically trapped state. Activation follows a spring-loaded mechanism not requiring further translation of other cellular factors in oocytes and is associated with unfolding of the inhibitory structure that blocks the tetramerization interface. Using a combination of biophysical methods as well as cell and ovary culture experiments we explain how TAp63α is kept inactive in the absence of DNA damage but causes rapid oocyte elimination in response to a few DNA double strand breaks thereby acting as the key quality control factor in maternal reproduction.
A consistent muscle activation strategy underlies crawling and swimming in Caenorhabditis elegans
(2014)
Although undulatory swimming is observed in many organisms, the neuromuscular basis for undulatory movement patterns is not well understood. To better understand the basis for the generation of these movement patterns, we studied muscle activity in the nematode Caenorhabditis elegans. Caenorhabditis elegans exhibits a range of locomotion patterns: in low viscosity fluids the undulation has a wavelength longer than the body and propagates rapidly, while in high viscosity fluids or on agar media the undulatory waves are shorter and slower. Theoretical treatment of observed behaviour has suggested a large change in force–posture relationships at different viscosities, but analysis of bend propagation suggests that short-range proprioceptive feedback is used to control and generate body bends. How muscles could be activated in a way consistent with both these results is unclear. We therefore combined automated worm tracking with calcium imaging to determine muscle activation strategy in a variety of external substrates. Remarkably, we observed that across locomotion patterns spanning a threefold change in wavelength, peak muscle activation occurs approximately 45° (1/8th of a cycle) ahead of peak midline curvature. Although the location of peak force is predicted to vary widely, the activation pattern is consistent with required force in a model incorporating putative length- and velocity-dependence of muscle strength. Furthermore, a linear combination of local curvature and velocity can match the pattern of activation. This suggests that proprioception can enable the worm to swim effectively while working within the limitations of muscle biomechanics and neural control.
In dieser Dissertation wurde die Rolle des Proteins Carboxypeptidase E (CPE) im Glioblastom (GBM) untersucht. Ursprünglich wurde CPE in der neuroendokrinen Regulation beschrieben, wo es die Reifung der meisten Neuropeptide und Hormone reguliert und somit Einfluss auf Stoffwechsel und humorale Effekte hat (Fricker et al., 1982; Fricker & Snyder, 1982 and 1983; Davidson & Hutton, 1987; Shen & Loh, 1997; Lou et al., 2005). Ab 1989 wurde CPE in unterschiedlichen Tumorentitäten nachgewiesen (Grimwood et al., 1989; Manser et al., 1991), jedoch ohne Hinweise, welche Bedeutung das Protein dort haben könnte. Erst im letzten Jahrzehnt konnten sowohl pro- als auch anti-tumorigene Wirkungen von CPE gezeigt werden. Die beschriebenen Wirkungen von CPE sind jedoch von dessen Isoform abhängig. Das ∂(delta)N-trunkierte CPE zeigte sich mit erhöhtem Tumorwachstum und schlechter Überlebensprognose in verschiedenen Krebsentitäten assoziiert (Murthy et al., 2010; Lee et al., 2011; Zhou et al., 2013). Im Gegensatz dazu verringerte sezerniertes CPE (sCPE) im Fibrosarkom und Glioblastom die Zellmigration, was einen anti-tumorigenen Effekt suggeriert (Höring et al., 2012; Murthy et al., 2013a). Die Molekularmechanismen, die für die Regulation der Migration zuständig sind, sind jedoch kaum untersucht. Die meisten Untersuchungen von sCPE in Normal- und Tumorgewebe beschränken sich hauptsächlich auf Apoptose und Zellüberleben (Skalka et al., 2013; Murthy et al., 2013b; Cheng et al., 2013; Selvaraj et al., 2015; Cheng et al., 2015). Die vorliegende Arbeit ist demzufolge die erste Studie, die sich dem Mechanismus der Migrationsregulation durch sCPE im Glioblastom widmet.
Humane Gliome stellen die größte und bösartigste Gruppe hirneigener Tumore dar. Bösartige Gliome sind höchst resistent gegen alle zurzeit verfügbaren Behandlungsmethoden. Einer der Hauptgründe dafür ist, dass die Tumorzellen durch diffuse Infiltration in das Gehirn einwandern können. Ferner sind Gliomzellen metabolisch sehr aktiv und können sich dadurch an schnell verändertes Milieu anpassen (Fack et al., 2015; Demeure et al., 2016). Über die grundlegenden Mechanismen für diese Art des infiltrierenden Tumorwachstums ist bisher noch nicht viel bekannt. Zurzeit sind nur wenige Schlüsselfaktoren beschrieben, die den sogenannten Mechanismus der Migration oder Proliferation ("go or grow") in bösartigen Tumoren beeinflussen: wenige Transkriptionsfaktoren, miRNAs sowie metabolische Faktoren. Interessanterweise, sind miRNAs zum Teil mit der Regulation des Metabolismus in Tumorzellen assoziiert. Eine vorangehende Studie aus unserem Labor hat sCPE aufgrund seines Potentials, Zellwanderung zu verringern, als einen weiteren Schlüsselfaktor identifiziert. Wir konnten zeigen, dass sCPE in der Gliomzelllinie LNT-229 zur einer differentiellen Regulation von Migration und Proliferation führt (Höring et al., 2012). Die vorliegende Arbeit widmet sich nun der Frage nach den genauen zugrundeliegenden Mechanismen, wie sCPE seine Effekte auf molekularer Ebene vermittelt. Darüber hinaus soll geklärt werden, ob sCPE auch in der metabolischen Adaptation eine Rolle spielt und dadurch ebenfalls die Gliomzellmigration beeinflußen kann.
In bacteria, the regulation of gene expression by cis-acting transcriptional riboswitches located in the 5'-untranslated regions of messenger RNA requires the temporal synchronization of RNA synthesis and ligand binding-dependent conformational refolding. Ligand binding to the aptamer domain of the riboswitch induces premature termination of the mRNA synthesis of ligand-associated genes due to the coupled formation of 3'-structural elements acting as terminators. To date, there has been no high resolution structural description of the concerted process of synthesis and ligand-induced restructuring of the regulatory RNA element. Here, we show that for the guanine-sensing xpt-pbuX riboswitch from Bacillus subtilis, the conformation of the full-length transcripts is static: it exclusively populates the functional off-state but cannot switch to the on-state, regardless of the presence or absence of ligand. We show that only the combined matching of transcription rates and ligand binding enables transcription intermediates to undergo ligand-dependent conformational refolding.