Conformational flexibility influences structure–function relationships in tyrosyl protein sulfotransferase-2

Tyrosine sulfation is a very important posttranslational modification of proteins. It is catalyzed by tyrosylprotein sulfotransferase and recently became increasingly important for biomedicine and pharmacy. An important insight about structure–activity relationships of human tyrosylprotein sulfotransferase has been received by elucidating the crystal structure, but there is still no understanding about how conformational flexibility and dynamics which are fundamental protein properties influence structure–function relationships of the enzyme. In order to provide this missing but crucially important knowledge we performed a comprehensive atomistic molecular dynamics study which revealed that (i) the conformational flexibility influences sensitively key structural determinants and interactions between the enzyme, the substrate and the cofactor; (ii) a more open conformation adopted by the substrate for binding in TPST 2; (iii) the mutations of key residues related with catalysis and binding change alter the enzyme structure and influence important interactions between the enzyme, the cofactor and the substrate

Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase

Many natural organic compounds with pharmaceutical applications, including antibiotics (chlortetracycline and vancomycin), antifungal compounds (pyrrolnitrin), and chemotherapeutics (salinosporamide A and rebeccamycin) are chlorinated. Halogenating enzymes like tryptophan 7-halogenase (PrnA) and tryptophan 5-halogenase (PyrH) perform regioselective halogenation of tryptophan. In this study, the conformational dynamics of two flavin-dependent tryptophan halogenasesPrnA and PyrHwas investigated through molecular dynamics simulations, which are in agreement with the crystallographic and kinetic experimental studies of both enzymes and provide further explanation of the experimental data at an atomistic level of accuracy. They show that the binding sites of the cofactor-flavin adenine dinucleotide and the substrate do not come into close proximity during the simulations, thus supporting an enzymatic mechanism without a direct contact between them. Two catalytically important active site residues, glutamate (E346/E354) and lysine (K79/K75) in PrnA and PyrH, respectively, were found to play a key role in positioning the proposed chlorinating agent, hypochlorous acid. The changes in the regioselectivity between PrnA and PyrH arise as a consequence of differences in the orientation of substrate in its binding site

Hydrodynamic electron flow in high-mobility wires

Hydrodynamic electron flow is experimentally observed in the differential resistance of electrostatically defined wires in the two-dimensional electron gas in (Al,Ga)As heterostructures. In these experiments current heating is used to induce a controlled increase in the number of electron-electron collisions in the wire. The interplay between the partly diffusive wire-boundary scattering and the electron-electron scattering leads first to an increase and then to a decrease of the resistance of the wire with increasing current. These effects are the electronic analog of Knudsen and Poiseuille flow in gas transport, respectively. The electron flow is studied theoretically through a Boltzmann transport equation, which includes impurity, electron-electron, and boundary scattering. A solution is obtained for arbitrary scattering parameters. By calculation of flow profiles inside the wire it is demonstrated how normal flow evolves into Poiseuille flow. The boundary-scattering parameters for the gate-defined wires can be deduced from the magnitude of the Knudsen effect. Good agreement between experiment and theory is obtained.Comment: 25 pages, RevTeX, 9 figure

How does conformational flexibility influence key structural features involved in activation of anaplastic lymphoma kinase?

Anaplastic Lymphoma Kinase (ALK) plays a major role in developing tumor processes and therefore has emerged as a validated therapeutic target. Applying atomistic molecular dynamics simulations on the wild type enzyme and the nine most frequently occurring and clinically important activation mutants we revealed important conformational effects on key interactions responsible for the activation of the enzyme

Spatial reorganization of putaminal dopamine D2-like receptors in cranial and hand dystonia

The putamen has a somatotopic organization of neurons identified by correspondence of firing rates with selected body part movements, as well as by complex, but organized, differential cortical projections onto putamen. In isolated focal dystonia, whole putaminal binding of dopamine D(2)-like receptor radioligands is quantitatively decreased, but it has not been known whether selected parts of the putamen are differentially affected depending upon the body part affected by dystonia. The radioligand [(18)F]spiperone binds predominantly to D(2)-like receptors in striatum. We hypothesized that the spatial location of [(18)F]spiperone binding within the putamen would differ in patients with dystonia limited to the hand versus the face, and we tested that hypothesis using positron emission tomography and magnetic resonance imaging. To address statistical and methodological concerns, we chose a straightforward but robust image analysis method. An automated algorithm located the peak location of [(18)F]spiperone binding within the striatum, relative to a brain atlas, in each of 14 patients with cranial dystonia and 8 patients with hand dystonia. The mean (left and right) |x|, y, and z coordinates of peak striatal binding for each patient were compared between groups by t test. The location of peak [(18)F]spiperone binding within the putamen differed significantly between groups (cranial dystonia z<hand dystonia z, p = 0.016). We conclude that in isolated focal dystonia, dopamine D(2)-like receptors are distributed differently in the putamen depending on the body part manifesting dystonia

Diffusion processes and growth on stepped metal surfaces

We study the dynamics of adatoms in a model of vicinal (11m) fcc metal surfaces. We examine the role of different diffusion mechanisms and their implications to surface growth. In particular, we study the effect of steps and kinks on adatom dynamics. We show that the existence of kinks is crucially important for adatom motion along and across steps. Our results are in agreement with recent experiments on Cu(100) and Cu(1,1,19) surfaces. The results also suggest that for some metals exotic diffusion mechanisms may be important for mass transport across the steps.Comment: 3 pages, revtex, complete file available from ftp://rock.helsinki.fi/pub/preprints/tft/ or at http://www.physics.helsinki.fi/tft/tft_preprints.html (to appear in Phys. Rev. B Rapid Comm.

Volatility return intervals analysis of the Japanese market

We investigate scaling and memory effects in return intervals between price volatilities above a certain threshold $q$ for the Japanese stock market using daily and intraday data sets. We find that the distribution of return intervals can be approximated by a scaling function that depends only on the ratio between the return interval $\tau$ and its mean $$. We also find memory effects such that a large (or small) return interval follows a large (or small) interval by investigating the conditional distribution and mean return interval. The results are similar to previous studies of other markets and indicate that similar statistical features appear in different financial markets. We also compare our results between the period before and after the big crash at the end of 1989. We find that scaling and memory effects of the return intervals show similar features although the statistical properties of the returns are different.Comment: 11 page

Stochastic Cellular Automata Model for Stock Market Dynamics

In the present work we introduce a stochastic cellular automata model in order to simulate the dynamics of the stock market. A direct percolation method is used to create a hierarchy of clusters of active traders on a two dimensional grid. Active traders are characterised by the decision to buy, (+1), or sell, (-1), a stock at a certain discrete time step. The remaining cells are inactive,(0). The trading dynamics is then determined by the stochastic interaction between traders belonging to the same cluster. Most of the stylized aspects of the financial market time series are reproduced by the model.Comment: 17 pages and 7 figure

Structure and Vibrations of the Vicinal Copper (211) Surface

We report a first principles theoretical study of the surface relaxation and lattice dynamics of the Cu(211) surface using the plane wave pseudopotential method. We find large atomic relaxations for the first several atomic layers near the step edges on this surface, and a substantial step-induced renormalization of the surface harmonic force constants. We use the results to study the harmonic fluctuations around the equilibrium structure and find three new step-derived features in the zone center vibrational spectrum. Comparison of these results with previous theoretical work and weith experimental studies using inelastic He scattering are reported.Comment: 6 Pages RevTex, 7 Figures in Postscrip