Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models

Understanding the structural mechanisms of protein–ligand binding and their dependence on protein sequence and conformation is of fundamental importance for biomedical research. Here we investigate the interplay of conformational change and ligand-binding kinetics for the serine protease Trypsin and its competitive inhibitor Benzamidine with an extensive set of 150 μs molecular dynamics simulation data, analysed using a Markov state model. Seven metastable conformations with different binding pocket structures are found that interconvert at timescales of tens of microseconds. These conformations differ in their substrate-binding affinities and binding/dissociation rates. For each metastable state, corresponding solved structures of Trypsin mutants or similar serine proteases are contained in the protein data bank. Thus, our wild-type simulations explore a space of conformations that can be individually stabilized by adding ligands or making suitable changes in protein sequence. These findings provide direct evidence of conformational plasticity in receptors

Pattern formation in binary fluid mixtures induced by short-range competing interactions

Molecular dynamics simulations and integral equation calculations of a simple equimolar mixture of diatomic molecules and monomers interacting via attractive and repulsive short-range potentials show the existence of pattern formation (microheterogeneity), mostly due to depletion forces away from the demixing region. Effective site-site potentials extracted from the pair correlation functions using an inverse Monte Carlo approach and an integral equation inversion procedure exhibit the features characteristic of a short-range attractive and long-range repulsive potential. When charges are incorporated into the model, this becomes a coarse grained representation of a room temperature ionic liquid, and as expected, intermediate range order becomes more pronounced and stable

Theoretical investigation of twin boundaries in WO3_3: Structure, properties and implications for superconductivity

We present a theoretical study of the structure and functionality of ferroelastic domain walls in tungsten trioxide, WO$_3$. WO$_3$ has a rich structural phase diagram, with the stability and properties of the various structural phases strongly affected both by temperature and by electron doping. The existence of superconductivity is of particular interest, with the underlying mechanism as of now not well understood. In addition, reports of enhanced superconductivity at structural domain walls are particularly intriguing. Focusing specifically on the orthorhombic $\beta$ phase, we calculate the structure and properties of the domain walls both with and without electron doping. We use two theoretical approaches: Landau-Ginzburg theory, with free energies constructed from symmetry considerations and parameters extracted from our first-principles density functional calculations, and direct calculation using large-scale, GPU-enabled density functional theory. We find that the structure of the $\beta$-phase domain walls resembles that of the bulk tetragonal $\alpha_1$ phase, and that the electronic charge tends to accumulate at the walls. Motivated by this finding, we perform ab initio computations of electron-phonon coupling in the bulk $\alpha_1$ structure and extract the superconducting critical temperatures , $T_c$, within Bardeen-Cooper-Schrieffer theory. Our results provide insight into the experimentally observed unusual trend of decreasing Tc with increasing electronic charge carrier concentration.Comment: 19 pages, 15 figure

El incidente diplomático como elemento transformador del orden jurídico y político internacional

 Sumario: 1. Introducción. 2. El incidente diplomático como acontecimiento. 3. El incidente diplomático como elemento narrativo. 4. El incidente diplomático como mecanismo de ajuste del orden internacional. 5. Conclusión

Proper actions, nonlinearity and homotopy theory

In dieser Arbeit wird die Erweiterung der Methoden der äquivarianten stabilen Homotopietheorie zu breiteren Kontexten untersucht. Die klassische Theorie voraussetzt Kompaktheit oder sogar Endlichkeit an der wirkenden Gruppe. Äquivariante Homotopie und Kohomotopie werden durch Spektren und analytische Methoden für eigentliche G-CW Komplexe konstruiert. Die Übereinstimmung mit der klassischen Definition, sowie zu einer von Lück 2005 veröffentlichten Konstruktion mittels Vektorraumbündeln wird bewiesen. Die Segal Vermutung wird in zwei Versionen verallgemeinert (für familien endlicher Untergruppen in diskreten Gruppen, bzw. für halb-einfache Liegruppen deren maximale kompakte Untergruppe keine Fundamentaldarstellung quaternionischen Typs aufweist). Eine bivariante , äquivariante homotopietheorie für C*-Algebren wird auch definiert

Variational Approach to Molecular Kinetics

The eigenvalues and eigenvectors of the molecular dynamics propagator (or transfer operator) contain the essential information about the molecular thermodynamics and kinetics. This includes the stationary distribution, the metastable states, and state-to-state transition rates. Here, we present a variational approach for computing these dominant eigenvalues and eigenvectors. This approach is analogous the variational approach used for computing stationary states in quantum mechanics. A corresponding method of linear variation is formulated. It is shown that the matrices needed for the linear variation method are correlation matrices that can be estimated from simple MD simulations for a given basis set. The method proposed here is thus to first define a basis set able to capture the relevant conformational transitions, then compute the respective correlation matrices, and then to compute their dominant eigenvalues and eigenvectors, thus obtaining the key ingredients of the slow kinetics

Experimental Long-Distance Decoy-State Quantum Key Distribution Based On Polarization Encoding

We demonstrate the decoy-state quantum key distribution (QKD) with one-way quantum communication in polarization space over 102km. Further, we simplify the experimental setup and use only one detector to implement the one-way decoy-state QKD over 75km, with the advantage to overcome the security loopholes due to the efficiency mismatch of detectors. Our experimental implementation can really offer the unconditionally secure final keys. We use 3 different intensities of 0, 0.2 and 0.6 for the pulses of source in our experiment. In order to eliminate the influences of polarization mode dispersion in the long-distance single-mode optical fiber, an automatic polarization compensation system is utilized to implement the active compensation.Comment: 4 pages,3 figure

PyEMMA 2: A Software Package for Estimation, Validation, and Analysis of Markov Models

Markov (state) models (MSMs) and related models of molecular kinetics have recently received a surge of interest as they can systematically reconcile simulation data from either a few long or many short simulations and allow us to analyze the essential metastable structures, thermodynamics, and kinetics of the molecular system under investigation. However, the estimation, validation, and analysis of such models is far from trivial and involves sophisticated and often numerically sensitive methods. In this work we present the opensource Python package PyEMMA (http://pyemma.org) that provides accurate and efficient algorithms for kinetic model construction. PyEMMA can read all common molecular dynamics data formats, helps in the selection of input features, provides easy access to dimension reduction algorithms such as principal component analysis (PCA) and time-lagged independent component analysis (TICA) and clustering algorithms such as k-means, and contains estimators for MSMs, hidden Markov models, and several other models. Systematic model validation and error calculation methods are provided. PyEMMA offers a wealth of analysis functions such that the user can conveniently compute molecular observables of interest. We have derived a systematic and accurate way to coarse-grain MSMs to few states and to illustrate the structures of the metastable states of the system. Plotting functions to produce a manuscript-ready presentation of the results are available. In this work, we demonstrate the features of the software and show new methodological concepts and results produced by PyEMMA