New insight into the architecture of oxy-anion pocket in unliganded conformation of GAT domains: A MD-simulation study

Human Guanine Monophosphate Synthetase (hGMPS) converts XMP to GMP, and acts as a bifunctional enzyme with N-terminal ``glutaminase'' (GAT) and C-terminal ``synthetase'' domain. The enzyme is identified as a potential target for anticancer and immunosuppressive therapies. GAT domain of enzyme plays central role in metabolism, and contains conserved catalytic residues Cys104, His190, and Glu192. MD simulation studies on GAT domain suggest that position of oxyanion in unliganded conformation is occupied by one conserved water molecule (W1), which also stabilizes that pocket. This position is occupied by a negatively charged atom of the substrate or ligand in ligand bound crystal structures. In fact, MD simulation study of Ser75 to Val indicates that W1 conserved water molecule is stabilized by Ser75, while Thr152, and His190 also act as anchor residues to maintain appropriate architecture of oxyanion pocket through water mediated H-bond interactions. Possibly, four conserved water molecules stabilize oxyanion hole in unliganded state, but they vacate these positions when the enzyme (hGMPS)-substrate complex is formed. Thus this study not only reveals functionally important role of conserved water molecules in GAT domain, but also highlights essential role of other non-catalytic residues such as Ser75 and Thr152 in this enzymatic domain. The results from this computational study could be of interest to experimental community and provide a testable hypothesis for experimental validation. Conserved sites of water molecules near and at oxyanion hole highlight structural importance of water molecules and suggest a rethink of the conventional definition of chemical geometry of inhibitor binding site.

Magnetic properties and magnetic domain structure of bulk glass forming Nd60Al10Fe20Co10 alloy

The transition from hard to soft magnetic behaviour with increasing quenching rate is shown for Nd60WAl10Fe20Co10 melt-spun ribbons with different thickness. Microstructure and magnetic domain structure of ribbons were studied by magnetic force microscopy (MFM). Particle sizes < 5 nm decreasing gradually with increasing quenching rate were deduced from topographic images which differ from large-scale magnetic domains with a periodicity of about 350 nm in all ribbons irrespective the coercivity. This indicates that the magnetic properties of the alloy are governed by interaction of small magnetic particles. It is concluded that the presence of short-range-ordered structures with a local ordering similar to the Al metastable Nd-Fe binary phase is responsible for the hard magnetic properties in samples subjected to relatively low quenching rate.

Domain structure of hard magnetic NdAlFeCo bulk metallic glass

Magnetic domain structure of hard magnetic Nd60Al10Fe20Co10 bulk metallic glass (BMG) has been studied by using magnetic force microscopy. In the magnetic force images it is shown that the exchange interaction type magnetic domains with a period of about 360 nm do exist in the BMG, which is believed to be associated with the appearance of hard-magnetic properties in this system. As the scale of the magnetic domain is much larger than the size of the short-range ordered atomic clusters existing in the BMG, it is believed that the large areas of magnetic contrast are actually a collection of a group of clusters aligned in parallel by strong exchange coupling interaction. After fully crystallization, the BMG exhibits paramagnetism. No obvious magnetic contrast is observed in the magnetic force images of fully crystallized samples, except for a small quantity of ferromagnetic crystalline phase with low coercivity and an average size of 900 nm.

Domain structure of a Nd60Al10Fe20Co10 bulk metallic glass

Magnetic domain structure of Nd60Al10Fe20Co10 bulk metallic glass (BMG) has been studied by using magnetic-force microscopy. In the magnetic-force images it is shown that the exchange-interaction-type magnetic domains with a period of about 360 nm do exist in the BMG, which is believed to be associated with the appearance of hard-magnetic properties in this system. The existence of the large-scale domains demonstrates that the magnetic moments of a great deal of short-scale ordered atomic clusters in the BMG have been aligned by exchange coupling. Annealing at 715 K leads to partial crystallization of the BMG. However, the exchange coupling is stronger in the annealed sample, which is considered to arise from the increase of transition-metal concentration in the amorphous phase due to the precipitation of Nd crystalline phase.

Flux closure vortexlike domain structures in ferroelectric thin films

Enhanced piezoresponse force microscopy was used to study flux closure vortexlike structures of 90° ferroelastic domains at the nanoscale in thin ferroelectric lead zirconium titanate (PZT) films. Using an external electric field, a vortexlike structure was induced far away from a grain boundary, indicating that physical edges are not necessary for nucleation contrary to previous suggestions. We demonstrate two different configurations of vortexlike structures, one of which has not been observed before. The stability of these structures is found to be size dependent, supporting previous predictions. © 2010 The American Physical Society.

Domains beyond the grain boundary

Thin films of inorganic materials are used in diverse applications, typically in polycrystalline form due to their relatively simple production. We have used enhanced piezoresponse force microscopy to investigate the domain distribution within neighbouring grains in thin polycrystalline films of the ferroelectric-ferroelastic system lead zirconate titanate (PZT). We demonstrate that domains are organized into areas with a correlated alignment of the ferroelastic and ferroelectric domains, spanning multiple grain boundaries. We present five typical arrangements of such structures: azimuthal, radial, gradient, and short- and long- range linear domain organizations. Moreover, we discuss the mechanical and electrical constraints that dictate these structures. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rigorous finite-time guarantees for optimization on continuous domains by simulated annealing

Simulated annealing is a popular method for approaching the solution of a global optimization problem. Existing results on its performance apply to discrete combinatorial optimization where the optimization variables can assume only a finite set of possible values. We introduce a new general formulation of simulated annealing which allows one to guarantee finite-time performance in the optimization of functions of continuous variables. The results hold universally for any optimization problem on a bounded domain and establish a connection between simulated annealing and up-to-date theory of convergence of Markov chain Monte Carlo methods on continuous domains. This work is inspired by the concept of finite-time learning with known accuracy and confidence developed in statistical learning theory.

Domain decomposition hybrid method for numerical simulation of bluff body flows:theoretical model and application

The discrete vortex method is not capable of precisely predicting the bluff body flow separation and the fine structure of flow field in the vicinity of the body surface. In order to make a theoretical improvement over the method and to reduce the difficulty in finite-difference solution of N-S equations at high Reynolds number, in the present paper, we suggest a new numerical simulation model and a theoretical method for domain decomposition hybrid combination of finite-difference method and vortex method. Specifically, the full flow. field is decomposed into two domains. In the region of O(R) near the body surface (R is the characteristic dimension of body), we use the finite-difference method to solve the N-S equations and in the exterior domain, we take the Lagrange-Euler vortex method. The connection and coupling conditions for flow in the two domains are established. The specific numerical scheme of this theoretical model is given. As a preliminary application, some numerical simulations for flows at Re=100 and Re-1000 about a circular cylinder are made, and compared with the finite-difference solution of N-S equations for full flow field and experimental results, and the stability of the solution against the change of the interface between the two domains is examined. The results show that the method of the present paper has the advantage of finite-difference solution for N-S equations in precisely predicting the fine structure of flow field, as well as the advantage of vortex method in efficiently computing the global characteristics of the separated flow. It saves computer time and reduces the amount of computation, as compared with pure N-S equation solution. The present method can be used for numerical simulation of bluff body flow at high Reynolds number and would exhibit even greater merit in that case.

Traces of nonsmooth functions on polyhedral domains

introduced in this paper are the definitions of the traces for a class of nonsmooth functions on polyhedral domains. By analyzing their properties we get the structures of these traces.

A Multiscale-Domain Decomposition Method for High Reynolds Number Flows

The high Reynolds number flow contains a wide range of length and time scales, and the flow domain can be divided into several sub-domains with different characteristic scales. In some sub-domains, the viscosity dissipation scale can only be considered in a certain direction; in some sub-domains, the viscosity dissipation scales need to be considered in all directions; in some sub-domains, the viscosity dissipation scales are unnecessary to be considered at all. For laminar boundary layer region, the characteristic length scales in the streamwise and normal directions are L and L Re-1/ 2 , respectively. The characteristic length scale and the velocity scale in the outer region of the boundary layer are L and U, respectively. In the neighborhood region of the separated point, the length scale l<domain decomposition method is developed for the high Reynolds number flow. First, the whole domain is decomposed to different sub-domains with the different characteristic scales. Then the different dominant equation of all sub-domains is defined according to the diffusion parabolized (DP) theory of viscous flow. Finally these different equations are solved simultaneously in whole computational region. For numerical tests of high Reynolds numerical flows, two-dimensional supersonic flows over rearward and frontward steps as well as an interaction flow between shock wave and boundary layer were solved numerically. The pressure distributions and local coefficients of skin friction on the wall are given. The numerical results obtained by the multiscale-domain decomposition algorithm are well agreement with those by NS equations. Comparing with the usual method of solving the Navier-Stokes equations in the whole flow, under the same numerical accuracy, the present multiscale domain decomposition method decreases CPU consuming about 20% and reflects the physical mechanism of practical flow more accurately.

Energy Functions And Basic Equations For Ferroelectrics

Energy functions (or characteristic functions) and basic equations for ferroelectrics in use today are given by those for ordinary dielectrics in the physical and mechanical communications. Based on these basic equations and energy functions, the finite element computation of the nonlinear behavior of the ferroelectrics has been carried out by several research groups. However, it is difficult to process the finite element computation further after domain switching, and the computation results are remarkably deviating from the experimental results. For the crack problem, the iterative solution of the finite element calculation could not converge and the solutions for fields near the crack tip oscillate. In order to finish the calculation smoothly, the finite element formulation should be modified to neglect the equivalent nodal load produced by spontaneous polarization gradient. Meanwhile, certain energy functions for ferroelectrics in use today are not compatible with the constitutive equations of ferroelectrics and need to be modified. This paper proposes a set of new formulae of the energy functions for ferroelectrics. With regard to the new formulae of the energy functions, the new basic equations for ferroelectrics are derived and can reasonably explain the question in the current finite element analysis for ferroelectrics.

Pharmacology and pore-forming domains of the cystic fibrosis transmembrane conductance regulator

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel member of the ATP-binding cassette (ABC) superfamily of membrane proteins. CFTR has two homologous halves, each consisting of six transmembrane spanning domains (TM) followed by a nucleotide binding fold, connected by a regulatory (R) domain. This thesis addresses the question of which domains are responsible for Cl^- selectivity, i.e., which domains line the channel pore.

To address this question, novel blockers of CFTR were characterized. CFTR was heterologously expressed in Xenopus oocytes to study the mechanism of block by two closely related arylaminobenzoates, diphenylamine-2-carboxylic acid (DPC) and flufenamic acid (FFA). Block by both is voltage-dependent, with a binding site ≈ 40% through the electric field of the membrane. DPC and FFA can both reach their binding site from either side of the membrane to produce a flickering block of CFTR single channels. In addition, DPC block is influenced by Cl^- concentration, and DPC blocks with a bimolecular forward binding rate and a unimolecular dissociation rate. Therefore, DPC and FFA are open-channel blockers of CFTR, and a residue of CFTR whose mutation affects their binding must line the pore.

Screening of site-directed mutants for altered DPC binding affinity reveals that TM-6 and TM-12 line the pore. Mutation of residue 5341 in TM-6 abolishes most DPC block, greatly reduces single-channel conductance, and alters the direction of current rectification. Additional residues are found in TM-6 (K335) and TM-12 (T1134) whose mutations weaken or strengthen DPC block; other mutations move the DPC binding site from TM-6 to TM-12. The strengthened block and lower conductance due to mutation T1134F is quantitated at the single-channel level. The geometry of DPC and of the residues mutated suggest α-helical structures for TM-6 and TM-12. Evidence is presented that the effects of the mutations are due to direct side-chain interaction, and not to allosteric effects propagated through the protein. Mutations are also made in TM-11, including mutation S1118F, which gives voltage-dependent current relaxations. The results may guide future studies on permeation through ABC transporters and through other Cl^- channels.

Molecular mechanism of sulfated carbohydrate recognition: structural and biochemical studies of the cysteine-rich domain of mannose receptor

Mannose receptor (MR) is widely expressed on macrophages, immature dendritic cells, and a variety of epithelial and endothelial cells. It is a 180 kD type I transmembrane receptor whose extracellular region consists of three parts: the amino-terminal cysteine-rich domain (Cys-MR); a fibronectin type II-like domain; and a series of eight tandem C-type lectin carbohydrate recognition domains (CRDs). Two portions of MR have distinct carbohydrate recognition properties: Cys-MR recognizes sulfated carbohydrates and the tandem CRD region binds terminal mannose, fucose, and N-acetyl-glucosamine (GlcNAc). The dual carbohydrate binding specificity allows MR to interact with sulfated and nonsulfated polysaccharide chains, and thereby facilitating the involvement of MR in immunological and physiological processes. The immunological functions of MR include antigen capturing (through binding non-sulfated carbohydrates) and antigen targeting (through binding sulfated carbohydrates), and the physiological roles include rapid clearance of circulatory luteinizing hormone (LH), which bears polysaccharide chains terminating with sulfated and non-sulfated carbohydrates.

We have crystallized and determined the X-ray structures of unliganded Cys-MR (2.0 Å) and Cys-MR complexed with different ligands, including Hepes (1.7 Å), 4SO_4-N-Acetylgalactosamine (4SO_4-GalNAc; 2.2 Å), 3SO_4-Lewis^x (2.2 Å), 3S04-Lewis^a (1.9 Å), and 6SO_4-GalNAc (2.5 Å). The overall structure of Cys-MR consists of 12 anti-parallel β-strands arranged in three lobes with approximate three fold internal symmetry. The structure contains three disulfide bonds, formed by the six cysteines in the Cys-MR sequence. The ligand-binding site is located in a neutral pocket within the third lobe, in which the sulfate group of ligand is buried. Our results show that optimal binding is achieved by a carbohydrate ligand with a sulfate group that anchors the ligand by forming numerous hydrogen bonds and a sugar ring that makes ring-stacking interactions with Trpll7 of CysMR. Using a fluorescence-based assay, we characterized the binding affinities between CysMR and its ligands, and rationalized the derived affinities based upon the crystal structures. These studies reveal the mechanism of sulfated carbohydrate recognition by Cys-MR and facilitate our understanding of the role of Cys-MR in MR recognition of its ligands.

General-domain compressible Navier-Stokes solvers exhibiting quasi-unconditional stability and high-order accuracy in space and time

This thesis presents a new class of solvers for the subsonic compressible Navier-Stokes equations in general two- and three-dimensional spatial domains. The proposed methodology incorporates: 1) A novel linear-cost implicit solver based on use of higher-order backward differentiation formulae (BDF) and the alternating direction implicit approach (ADI); 2) A fast explicit solver; 3) Dispersionless spectral spatial discretizations; and 4) A domain decomposition strategy that negotiates the interactions between the implicit and explicit domains. In particular, the implicit methodology is quasi-unconditionally stable (it does not suffer from CFL constraints for adequately resolved flows), and it can deliver orders of time accuracy between two and six in the presence of general boundary conditions. In fact this thesis presents, for the first time in the literature, high-order time-convergence curves for Navier-Stokes solvers based on the ADI strategy---previous ADI solvers for the Navier-Stokes equations have not demonstrated orders of temporal accuracy higher than one. An extended discussion is presented in this thesis which places on a solid theoretical basis the observed quasi-unconditional stability of the methods of orders two through six. The performance of the proposed solvers is favorable. For example, a two-dimensional rough-surface configuration including boundary layer effects at Reynolds number equal to one million and Mach number 0.85 (with a well-resolved boundary layer, run up to a sufficiently long time that single vortices travel the entire spatial extent of the domain, and with spatial mesh sizes near the wall of the order of one hundred-thousandth the length of the domain) was successfully tackled in a relatively short (approximately thirty-hour) single-core run; for such discretizations an explicit solver would require truly prohibitive computing times. As demonstrated via a variety of numerical experiments in two- and three-dimensions, further, the proposed multi-domain parallel implicit-explicit implementations exhibit high-order convergence in space and time, useful stability properties, limited dispersion, and high parallel efficiency.