A New Method for Ligand-supported Homology Modelling of Protein Binding Sites: Development and Application to the neurokinin-1 receptor

In this thesis, a novel strategy (MOBILE (Modelling Binding Sites Including Ligand Information Explicitly)) was developed that models protein binding-sites simultaneously considering information about the binding mode of bioactive ligands during the homology modelling process. As a result, protein binding-site models of higher accuracy and relevance can be generated. Starting with the (crystal) structure of one or more template proteins, in the first step several preliminary homology models of the target protein are generated using the homology modelling program MODELLER. Ligands are then placed into these preliminary models using different strategies depending on the amount of experimental information about the binding mode of the ligands. (1.) If a ligand is known to bind to the target protein and the crystal structure of the protein-ligand complex with the related template protein is available, it can be assumed that the ligand binding modes are similar in the target and template protein. Accordingly, ligands are then transferred among these structures keeping their orientation as a restraint for the subsequent modelling process. (2.) If no complex crystal structure with the template is available, the ligand(s) can be placed into the template protein structure by docking, and the resulting orientation can then be used to restrain the following protein modelling process. Alternatively, (3.) in cases where knowledge about the binding mode cannot be inferred by the template protein, ligand docking is performed into an ensemble of homology models. The ligands are placed into a crude binding-site representation via docking into averaged property fields derived from knowledge-based potentials. Once the ligands are placed, a new set of homology models is generated. However, in this step, ligand information is considered as additional restraint in terms of the knowledge-based DrugScore protein-ligand atom pair potentials. Consulting a large ensemble of produced models exhibiting di erent side-chain rotamers for the binding-site residues, a composite picture is assembled considering the individually best scored rotamers with respect to the ligand. After a local force-field optimisation, the obtained binding-site models can be used for structure-based drug design

Yoctosecond photon pulses from quark-gluon plasmas

Present ultra-fast laser optics is at the frontier between atto- and zeptosecond photon pulses, giving rise to unprecedented applications. We show that high-energetic photon pulses down to the yoctosecond timescale can be produced in heavy ion collisions. We focus on photons produced during the initial phase of the expanding quark-gluon plasma. We study how the time evolution and properties of the plasma may influence the duration and shape of the photon pulse. Prospects for achieving double peak structures suitable for pump-probe experiments at the yoctosecond timescale are discussed.Comment: 4 pages, 2 figures; final version as accepted by PR

Streaking At High Energies With Electrons And Positrons

State-of-the-art attosecond metrology deals with the detection and characterization of photon pulses with typical energies up to the hundreds of eV and time resolution of several tens of attoseconds. Such short pulses are used for example to control the motion of electrons on the atomic scale or to measure inner-shell atomic dynamics. The next challenge of time-resolving the inner-nuclear dynamics, transient meson states and resonances requires photon pulses below attosecond duration and with energies exceeding the MeV scale. Here we discuss a detection scheme for time-resolving high-energy gamma ray pulses down to the zeptosecond timescale. The scheme is based on the concept of attosecond streak imaging, but instead of conversion of photons into electrons in a nonlinear medium, the high-energy process of electron-positron pair creation is utilized. These pairs are produced in vacuum through the collision of a test pulse to be characterized with an intense laser pulse, and they acquire additional energy and momentum depending on their phase in the streaking pulse at the moment of production. A coincidence measurement of the electron and positron momenta after the interaction provides information on the pair production phase within the streaking pulse. We examine the limitations imposed by quantum radiation reaction in multiphoton Compton scattering on this detection scheme, and discuss other necessary conditions to render the scheme feasible in the upcoming Extreme Light Infrastructure (ELI) laser facility.Comment: 6 pages, 2 figures, contribution to the AIP proceedings of "Light at Extreme Intensities" (LEI 2011), Szeged, Hungary, Nov 14-18, 201

Charge Transport in Single Au|Alkanedithiol|Au Junctions: Coordination Geometries and Conformational Degrees of Freedom

Recent STM molecular break-junction experiments have revealed multiple series of peaks in the conductance histograms of alkanedithiols. To resolve a current controversy, we present here an in-depth study of charge transport properties of Au|alkanedithiol|Au junctions. Conductance histograms extracted from our STM measurements unambiguously confirm features showing more than one set of junction configurations. Based on quantum chemistry calculations, we propose that certain combinations of different sulfur-gold couplings and trans/gauche conformations act as the driving agents. The present study may have implications for experimental methodology: whenever conductances of different junction conformations are not statistically independent, the conductance histogram technique can exhibit a single series only, even though a much larger abundance of microscopic realizations exists.Comment: 19 pages, 9 figures, 1 table; published versio

Statistics of Conductances and Subleading Corrections to Scaling near the Integer Quantum Hall Plateau Transition

We study the critical behavior near the integer quantum Hall plateau transition by focusing on the multifractal (MF) exponents $X_q$ describing the scaling of the disorder-average moments of the point contact conductance $T$ between two points of the sample, within the Chalker-Coddington network model. Past analytical work has related the exponents $X_q$ to the MF exponents $\Delta_q$ of the local density of states (LDOS). To verify this relation, we numerically determine the exponents $X_q$ with high accuracy. We thereby provide, at the same time, independent numerical results for the MF exponents $\Delta_q$ for the LDOS. The presence of subleading corrections to scaling makes such determination directly from scaling of the moments of $T$ virtually impossible. We overcome this difficulty by using two recent advances. First, we construct pure scaling operators for the moments of $T$ which have precisely the same leading scaling behavior, but no subleading contributions. Secondly, we take into account corrections to scaling from irrelevant (in the renormalization group sense) scaling fields by employing a numerical technique ("stability map") recently developed by us. We thereby numerically confirm the relation between the two sets of exponents, $X_q$ (point contact conductances) and $\Delta_q$ (LDOS), and also determine the leading irrelevant (corrections to scaling) exponent $y$ as well as other subleading exponents. Our results suggest a way to access multifractality in an experimental setting.Comment: 7 pages and 4 figures, plus Supplemental materia

Boneless Pose Editing and Animation

Abstract. In this paper, we propose a pose editing and animation method for triangulated surfaces based on a user controlled partitioning of the model into deformable parts and rigid parts which are denoted handles. In our pose editing system, the user can sculpt a set of poses simply by transforming the handles for each pose. Using Laplacian editing, the deformable parts are deformed to match the handles. In our animation system the user can constrain one or several handles in order to define a new pose. New poses are interpolated from the examples poses, by solving a small non-linear optimization problem in order to obtain the interpolation weights. While the system can be used simply for building poses, it is also an animation system. The user can specify a path for a given constraint and the model is animated correspondingly.

Change in intraindividual ICHD-II headache diagnosis over time: A follow-up of the DMKG headache study

Background: Change in headache diagnoses over time within the same individual is not well studied in the adult population. In this study, we prospectively examined the individual variation of migraine and tension-type headache (TTH) diagnoses over time. Methods: As part of the epidemiological Deutsche Migrane und Kopfschmerzgesellschaft (DMKG) headache study, 1312 participants were personally interviewed and 1122 responded to a second mailed questionnaire 2.2 years later. Headaches were assigned to migraine or TTH at two different points in time using the International Headache Classification, ICHD-II. We used broad (definite and probable subtypes) and strict (only definite type) definitions of migraine and TTH. Results: Using the broad definition increased the reproducibility of migraine diagnosis from 48.0% to 62.0% and of TTH from 59.0% to 65.0%. A constant TTH diagnosis was related to a higher social status (OR 2.81; 95% CI 1.43-5.53) a higher level of education (OR 1.96; 95% CI 1.00-3.85) and physical inactivity (OR 2.28; 95% CI 1.16-4.49). A constant diagnosis of definite migraine was associated with severe headache (OR 2.64; 95% CI 0.97-7.21) and frequent use of headache medication (OR 4.73; 95% CI 0.95-23.60). The result that coexisting TTH decreased the likelihood of a constant migraine (OR 0.29; 95% CI 0.10-0.85) is assumed to indicate response variability. Conclusions: In epidemiological studies, definite and probable subtypes should be included in the diagnosis to increase the diagnostic accuracy