An Allosteric Signaling Pathway of Human 3-Phosphoglycerate Kinase from Force Distribution Analysis

3-Phosphogycerate kinase (PGK) is a two domain enzyme, which transfers a phosphate group between its two substrates, 1,3-bisphosphoglycerate bound to the N-domain and ADP bound to the C-domain. Indispensable for the phosphoryl transfer reaction is a large conformational change from an inactive open to an active closed conformation via a hinge motion that should bring substrates into close proximity. The allosteric pathway resulting in the active closed conformation has only been partially uncovered. Using Molecular Dynamics simulations combined with Force Distribution Analysis (FDA), we describe an allosteric pathway, which connects the substrate binding sites to the interdomain hinge region. Glu192 of alpha-helix 7 and Gly394 of loop L14 act as hinge points, at which these two secondary structure elements straighten, thereby moving the substrate-binding domains towards each other. The long-range allosteric pathway regulating hPGK catalytic activity, which is partially validated and can be further tested by mutagenesis, highlights the virtue of monitoring internal forces to reveal signal propagation, even if only minor conformational distortions, such as helix bending, initiate the large functional rearrangement of the macromolecule. © 2014 Palmai et al

Investigating Performance of Bonded Concrete Overlays

A bonded concrete overlay (BCO) is a concrete pavement rehabilitation method used to extend the life of an existing concrete pavement. The BCO should bond fully with the existing concrete, leading to a thicker composite pavement section, a much stiffer pavement, and a considerable decrease in pavement stresses. For one project, cost estimates for a BCO were half as much as for full-depth replacement of a pavement. In some cases BCOs have delaminated shortly after construction. This paper proposes a framework for identifying the causes of early age delamination in BCOs. The early age behavior of newly constructed BCOs is examined. The factors affecting the long-term performance of the BCO are the quality of the surface preparation, the materials used in the BCO, and the curing of the BCO. Weather monitoring during BCO construction is recommended. Methods of detecting and mapping delaminations are discussed. Several BCO delamination case studies are analyzed using this framework. The model is useful not only for investigating BCO performance but also for understanding and preparing BCO construction specifications

The d' dibaryon in the quark-delocalization, color-screening model

We study the questions of the existence and mass of the proposed $d' (IJ^P=00^-)$ dibaryon in the quark-delocalization, color-screening model (QDCSM). The transformation between physical and symmetry bases has been extended to the cases beyond the SU(2) orbital symmetry. Using parameters fixed by baryon properties and $NN$ scattering, we find a mild attraction in the $IJ^P=00^-$ channel, but it is not strong enough to form a deeply bound state as proposed for the $d'$ state. Nor does the (isospin) I=2 N$\Delta$ configuration have a deeply bound state. These results show that if a narrow dibaryon $d'$ state does exist, it must have a more complicated structure.Comment: 12 pp. latex, no figs., 2 tables, additional refs., Report-no was adde

Resonant behaviour in double charge exchange reaction of \pi^+ mesons on the nuclear photoemulsion

The invariant mass spectra of the $pp\pi^-$ and $pp$ systems produced in the double charge exchange (DCX) of positively charged pions on photoemulsion are analysed. A pronounced peak is observed in the $pp\pi^-$ invariant mass spectrum, while the $M_{pp}$ spectrum exhibits a strong Migdal-Watson effect of the proton-proton final state interaction. These findings are in favor of the $NN$-decoupled $NN\pi$ pseudoscalar resonance with T=0 called $d'$.Comment: 13 pages, 5 figures, revised versio

Investigating Performance of Bonded Concrete Overlays

A bonded concrete overlay (BCO) is a concrete pavement rehabilitation method used to extend the life of an existing concrete pavement. The BCO should bond fully with the existing concrete, leading to a thicker composite pavement section, a much stiffer pavement, and a considerable decrease in pavement stresses. For one project, cost estimates for a BCO were half as much as for full-depth replacement of a pavement. In some cases BCOs have delaminated shortly after construction. This paper proposes a framework for identifying the causes of early age delamination in BCOs. The early age behavior of newly constructed BCOs is examined. The factors affecting the long-term performance of the BCO are the quality of the surface preparation, the materials used in the BCO, and the curing of the BCO. Weather monitoring during BCO construction is recommended. Methods of detecting and mapping delaminations are discussed. Several BCO delamination case studies are analyzed using this framework. The model is useful not only for investigating BCO performance but also for understanding and preparing BCO construction specifications

Electrostatic interactions contribute to the control of intramolecular thiol-disulfide isomerization in a protein

The roles of structural factors and of electrostatic interactions with the environment on the outcome of thiol–disulfide exchange reactions were investigated in a mutated immunoglobulin domain (I27*) under mechanical stress. An extensive ensemble of molecular dynamics trajectories was generated by means of QM/MM simulations for a total sampling of 5.7 μs. A significant number of thiol–disulfide exchanges were observed, and the Cys32 thiolate preferred to attack Cys55 over Cys24, in agreement with previous experimental and computational studies. The structural features as well as electronic structures of the thiol–disulfide system along the reaction were analyzed, as were the electrostatic interactions with the environment. The previous findings of better accessibility of Cys55 were confirmed. Additionally, the reaction was found to be directed by the electrostatic interactions of the involved sulfur atoms with the molecular environment. The relationships of atomic charges, which stem from the electrostatic interactions, lead to the kinetic preference of the attack on Cys55. Further, QM/MM metadynamics simulations of thiol–disulfide exchange in a small model system with varied artificial external electric potentials revealed changes in reaction kinetics of the same magnitude as in I27*. Therefore, the electrostatic interactions are confirmed to play a role in the regioselectivity of the thiol–disulfide exchange reactions in the protein

The Fringe Detection Laser Metrology for the GRAVITY Interferometer at the VLTI

Interferometric measurements of optical path length differences of stars over large baselines can deliver extremely accurate astrometric data. The interferometer GRAVITY will simultaneously measure two objects in the field of view of the Very Large Telescope Interferometer (VLTI) of the European Southern Observatory (ESO) and determine their angular separation to a precision of 10 micro arcseconds in only 5 minutes. To perform the astrometric measurement with such a high accuracy, the differential path length through the VLTI and the instrument has to be measured (and tracked since Earth's rotation will permanently change it) by a laser metrology to an even higher level of accuracy (corresponding to 1 nm in 3 minutes). Usually, heterodyne differential path techniques are used for nanometer precision measurements, but with these methods it is difficult to track the full beam size and to follow the light path up to the primary mirror of the telescope. Here, we present the preliminary design of a differential path metrology system, developed within the GRAVITY project. It measures the instrumental differential path over the full pupil size and up to the entrance pupil location. The differential phase is measured by detecting the laser fringe pattern both on the telescopes' secondary mirrors as well as after reflection at the primary mirror. Based on our proposed design we evaluate the phase measurement accuracy based on a full budget of possible statistical and systematic errors. We show that this metrology design fulfills the high precision requirement of GRAVITY.Comment: Proc. SPIE in pres

Spontaneous symmetry breaking in the colored Hubbard model

The Hubbard model is reformulated in terms of different ``colored'' fermion species for the electrons or holes at different lattice sites. Antiferromagnetic ordering or d-wave superconductivity can then be described in terms of translationally invariant expectation values for colored composite scalar fields. A suitable mean field approximation for the two dimensional colored Hubbard model shows indeed phases with antiferromagnetic ordering or d-wave superconductivity at low temperature. At low enough temperature the transition to the antiferromagnetic phase is of first order. The present formulation also allows an easy extension to more complicated microscopic interactions.Comment: 19 pages, 5 figure

Force-Sensitive Autoinhibition of the von Willebrand Factor ls Mediated by Interdomain Interactions

Von Willebrand factor (VWF) plays a central role in hemostasis. Triggered by shear-stress, it adheres to platelets at sites of vascular injury. Inactivation of VWF has been associated to the shielding of its adhesion sites and proteolytic cleavage. However, the molecular nature of this shielding and its coupling to cleavage under shear-forces in flowing blood remain unknown. In this study, we describe, to our knowledge, a new force-sensory mechanism for VWF-platelet binding, which addresses these questions, based on a combination of molecular dynamics (MD) simulations, atomic force microscopy (AFM), and microfluidic experiments. Our MD simulations demonstrate that the VWF A2 domain targets a specific region at the VWF A1 domain, corresponding to the binding site of the platelet glycoprotein Ibα (GPIbα) receptor, thereby causing its blockage. This implies autoinhibition of the VWF for the binding of platelets mediated by the A1-A2 protein-protein interaction. During force-probe MD simulations, a stretching force dissociated the A1A2 complex, thereby unblocking the GPIbα binding site. Dissociation was found to be coupled to the unfolding of the A2 domain, with dissociation predominantly occurring before exposure of the cleavage site in A2, an observation that is supported by our AFM experiments. This suggests that the A2 domain prevents platelet binding in a force-dependent manner, ensuring that VWF initiates hemostasis before inactivation by proteolytic cleavage. Microfluidic experiments with an A2-deletion VWF mutant resulted in increased platelet binding, corroborating the key autoinhibitory role of the A2 domain within VWF multimers. Overall, autoinhibition of VWF mediated by force-dependent interdomain interactions offers the molecular basis for the shear-sensitive growth of VWF-platelet aggregates, and might be similarly involved in shear-induced VWF self-aggregation and other force-sensing functions in hemostasis