Using Correlated Parameters for Improved Ranking of Protein-Protein Docking Decoys

A successful protein-protein docking study culminates in identification of decoys at top ranks with near-native quaternary structures. However, this task remains enigmatic because no generalized scoring functions exist that effectively infer decoys according to the similarity to near-native quaternary structures. Difficulties arise because of the highly irregular nature of the protein surface and the significant variation of the nonbonding and solvation energies based on the chemical composition of the protein-protein interface. In this work, we describe a novel method combining an interface-size filter, a regression model for geometric compatibility (based on two correlated surface and packing parameters), and normalized interaction energy (calculated from correlated nonbonded and solvation energies), to effectively rank decoys from a set of 10,000 decoys. Tests on 30 unbound binary protein-protein complexes show that in 16 cases we can identify at least one decoy in top three ranks having <= 10 angstrom backbone root mean square deviation from true binding geometry. Comparisons with other state-of-art methods confirm the improved ranking power of our method without the use of any experiment-guided restraints, evolutionary information, statistical propensities, or modified interaction energy equations. Tests on 118 less-difficult bound binary protein-protein complexes with <= 35% sequence redundancy at the interface showed that in 77% cases, at least 1 in 10,000 decoys were identified with <= 5 angstrom backbone root mean square deviation from true geometry at first rank. The work will promote the use of new concepts where correlations among parameters provide more robust scoring models. It will facilitate studies involving molecular interactions, including modeling of large macromolecular assemblies and protein structure prediction. (C) 2010 Wiley Periodicals, Inc. J Comput Chem 32: 787-796, 2011.

DockYard-a repository to assist modeling of protein-protein docking

In the absence of interlogs, building docking models is a time intensive task, involving generation of a large pool of docking decoys followed by refinement and screening to identify near native docking solutions. This limits the researcher interested in building docking methods with the choice of benchmarking only a limited number of protein complexes. We have created a repository called dockYard (http://pallab.serc.iisc.ernet.in/dockYard), that allows modelers interested in protein-protein interaction to access large volume of information on protein dimers and their interlogs, and also download decoys for their work if they are interested in building modeling methods. dockYard currently offers four categories of docking decoys derived from: Bound (native dimer co-crystallized), Unbound (individual subunits are crystallized, as well as the target dimer), Variants (match the previous two categories in at least one subunit with 100% sequence identity), and Interlogs (match the previous categories in at least one subunit with >= 90% or >= 50% sequence identity). The web service offers options for full or selective download based on search parameters. Our portal also serves as a repository to modelers who may want to share their decoy sets with the community.

Stochastic modelling of flexible manufacturing systems

Mathematical modelling plays a vital role in the design, planning and operation of flexible manufacturing systems (FMSs). In this paper, attention is focused on stochastic modelling of FMSs using Markov chains, queueing networks, and stochastic Petri nets. We bring out the role of these modelling tools in FMS performance evaluation through several illustrative examples and provide a critical comparative evaluation. We also include a discussion on the modelling of deadlocks which constitute an important source of performance degradation in fully automated FMSs.

Stability of the viscous flow of a fluid through a flexible tube

The stability of the Hagen-Poiseuille flow of a Newtonian fluid in a tube of radius R surrounded by an incompressible viscoelastic medium of radius R < r < HR is analysed in the high Reynolds number regime. The dimensionless numbers that affect the fluid flow are the Reynolds number Re = (rho VR/eta), the ratio of the viscosities of the wall and fluid eta(r) = (eta(s)/eta), the ratio of radii H and the dimensionless velocity Gamma = (rho V-2/G)(1/2). Here rho is the density of the fluid, G is the coefficient of elasticity of the wall and V is the maximum fluid velocity at the centre of the tube. In the high Reynolds number regime, an asymptotic expansion in the small parameter epsilon = (1/Re) is employed. In the leading approximation, the viscous effects are neglected and there is a balance between the inertial stresses in the fluid and the elastic stresses in the medium. There are multiple solutions for the leading-order growth rate s((0)), all of which are imaginary, indicating that the fluctuations are neutrally stable, since there is no viscous dissipation of energy or transfer of energy from the mean flow to the fluctuations due to the Reynolds stress. There is an O(epsilon(1/2)) correction to the growth rate, s((1)), due to the presence of a wall layer of thickness epsilon(1/2)R where the viscous stresses are O(epsilon(1/2)) smaller than the inertial stresses. An energy balance analysis indicates that the transfer of energy from the mean flow to the fluctuations due to the Reynolds stress in the wall layer is exactly cancelled by an opposite transfer of equal magnitude due to the deformation work done at the interface, and there is no net transfer from the mean flow to the fluctuations. Consequently, the fluctuations are stabilized by the viscous dissipation in the wall layer, and the real part of s(1) is negative. However, there are certain values of Gamma and wavenumber k where s((1)) = 0. At these points, the wall layer amplitude becomes zero because the tangential velocity boundary condition is identically satisfied by the inviscid flow solution. The real part of the O(epsilon) correction to the growth rate s((2)) turns out to be negative at these points, indicating a small stabilizing effect due to the dissipation in the bulk of the fluid and the wall material. It is found that the minimum value of s((2)) increases proportional to (H-1)(-2) for (H-1) much less than 1 (thickness of wall much less than the tube radius), and decreases proportional to H-4 for H much greater than 1. The damping rate for the inviscid modes is smaller than that for the viscous wall and centre modes in a rigid tube, which have been determined previously using a singular perturbation analysis. Therefore, these are the most unstable modes in the flow through a flexible tube

Stability of the viscous flow of a fluid through a flexible tube

The stability of Hagen-Poiseuille flow of a Newtonian fluid of viscosity eta in a tube of radius R surrounded by a viscoelastic medium of elasticity G and viscosity eta(s) occupying the annulus R < r < HR is determined using a linear stability analysis. The inertia of the fluid and the medium are neglected, and the mass and momentum conservation equations for the fluid and wall are linear. The only coupling between the mean flow and fluctuations enters via an additional term in the boundary condition for the tangential velocity at the interface, due to the discontinuity in the strain rate in the mean flow at the surface. This additional term is responsible for destabilizing the surface when the mean velocity increases beyond a transition value, and the physical mechanism driving the instability is the transfer of energy from the mean flow to the fluctuations due to the work done by the mean flow at the interface. The transition velocity Gamma(t) for the presence of surface instabilities depends on the wavenumber k and three dimensionless parameters: the ratio of the solid and fluid viscosities eta(r) = (eta(s)/eta), the capillary number Lambda = (T/GR) and the ratio of radii H, where T is the surface tension of the interface. For eta(r) = 0 and Lambda = 0, the transition velocity Gamma(t) diverges in the limits k much less than 1 and k much greater than 1, and has a minimum for finite k. The qualitative behaviour of the transition velocity is the same for Lambda > 0 and eta(r) = 0, though there is an increase in Gamma(t) in the limit k much greater than 1. When the viscosity of the surface is non-zero (eta(r) > 0), however, there is a qualitative change in the Gamma(t) vs. k curves. For eta(r) < 1, the transition velocity Gamma(t) is finite only when k is greater than a minimum value k(min), while perturbations with wavenumber k < k(min) are stable even for Gamma--> infinity. For eta(r) > 1, Gamma(t) is finite only for k(min) < k < k(max), while perturbations with wavenumber k < k(min) or k > k(max) are stable in the limit Gamma--> infinity. As H decreases or eta(r) increases, the difference k(max)- k(min) decreases. At minimum value H = H-min, which is a function of eta(r), the difference k(max)-k(min) = 0, and for H < H-min, perturbations of all wavenumbers are stable even in the limit Gamma--> infinity. The calculations indicate that H-min shows a strong divergence proportional to exp (0.0832 eta(r)(2)) for eta(r) much greater than 1.

Synthesis of path generating flexible-link mechanisms

Flexible-link mechanisms are those linkage mechanisms (or structures) which are capable of motion by virtue of elastic deformation of one or more;links. In such mechanisms a single flexible link; can replace several rigid links and joints resulting in fewer links, fewer pin joints, reduced overall weight and reduced mechanical error. In spite of such clear advantages, contributions toward flexible-link mechanisms remain very scarce. The area of flexible-link mechanisms offers much scope for further exploration. This paper attempts to show the potential of flexible-link mechanisms in accomplishing a kinematic task like path generation. Synthesis of a four-bar mechanism with a flexible rocker for circular and straight line path generation is carried out. Displacement analysis of the structure is carried out using finite element method (FEM) and synthesis is formulated and solved as an optimization problem. Several numerical examples are presented for illustration. Based on the results obtained with these examples, the flexible-link mechanism considered shows good promise for-path generation.

Nematogens with more flexible chains than aromatic rings in the core

Mesogens containing four rings in the main core can accommodate one terminal and two nearby lateral chains on each outside aromatic ring. These compounds containing six chains present an enantiotropic nematic range which is influenced by the rigidity of the links. The conformational behaviour of the first methyleneoxy group within the chains was investigated by one and two dimensional C-13 NMR. The sign of the jump in chemical shifts when entering the nematic phase indicates the folding of each lateral branch. Dipolar oscillations during cross-polarization contact provide the values of the bond order parameter. The two First lateral fragments do not behave in the same way, demonstrating the influence of the fragment along which the chain is back: folded.

Stability of non-parabolic flow in a flexible tube

Flows with velocity profiles very different from the parabolic velocity profile can occur in the entrance region of a tube as well as in tubes with converging/diverging cross-sections. In this paper, asymptotic and numerical studies are undertaken to analyse the temporal stability of such 'non-parabolic' flows in a flexible tube in the limit of high Reynolds numbers. Two specific cases are considered: (i) developing flow in a flexible tube; (ii) flow in a slightly converging flexible tube. Though the mean velocity profile contains both axial and radial components, the flow is assumed to be locally parallel in the stability analysis. The fluid is Newtonian and incompressible, while the flexible wall is modelled as a viscoelastic solid. A high Reynolds number asymptotic analysis shows that the non-parabolic velocity profiles can become unstable in the inviscid limit. This inviscid instability is qualitatively different from that observed in previous studies on the stability of parabolic flow in a flexible tube, and from the instability of developing flow in a rigid tube. The results of the asymptotic analysis are extended numerically to the moderate Reynolds number regime. The numerical results reveal that the developing flow could be unstable at much lower Reynolds numbers than the parabolic flow, and hence this instability can be important in destabilizing the fluid flow through flexible tubes at moderate and high Reynolds number. For flow in a slightly converging tube, even small deviations from the parabolic profile are found to be sufficient for the present instability mechanism to be operative. The dominant non-parallel effects are incorporated using an asymptotic analysis, and this indicates that non-parallel effects do not significantly affect the neutral stability curves. The viscosity of the wall medium is found to have a stabilizing effect on this instability.

PRUNE and PROBE-two modular web services for protein-protein docking

The protein-protein docking programs typically perform four major tasks: (i) generation of docking poses, (ii) selecting a subset of poses, (iii) their structural refinement and (iv) scoring, ranking for the final assessment of the true quaternary structure. Although the tasks can be integrated or performed in a serial order, they are by nature modular, allowing an opportunity to substitute one algorithm with another. We have implemented two modular web services, (i) PRUNE: to select a subset of docking poses generated during sampling search (http://pallab.serc.iisc.ernet.in/prune) and (ii) PROBE: to refine, score and rank them (http://pallab.serc.iisc.ernet.in/probe). The former uses a new interface area based edge-scoring function to eliminate > 95% of the poses generated during docking search. In contrast to other multi-parameter-based screening functions, this single parameter based elimination reduces the computational time significantly, in addition to increasing the chances of selecting native-like models in the top rank list. The PROBE server performs ranking of pruned poses, after structure refinement and scoring using a regression model for geometric compatibility, and normalized interaction energy. While web-service similar to PROBE is infrequent, no web-service akin to PRUNE has been described before. Both the servers are publicly accessible and free for use.

Solid state structural and solution studies on the formation of a flexible cavity for anions by copper(I) and 1,2-bis(diphenylphosphino)ethane

Copper(l) complexes of 1,2-bis(diphenylphosphino)ethane (dppe) with a stoichiometry Cu-2(dppe)(3)(X)(2) [X- = CN- (1), SCN- (2), NO3- (3)] are obtained from direct reactions of CuX and dppe. The complexes are structurally and spectroscopically (NMR and IR) characterized. The structure of the [Cu-2(dPPe)(3)](2+) dication is similar to the structural motif observed in many other complexes with a chelating dppe and a bridging dppe connecting two copper centers. In complexes 1 -3, the anions are confined to the cavity formed by the phosphines which force a monodentate coordination mode despite the predominant bidentate/bridging character of the anions. The coordination angles rather than the thermochemical radii dictate the steric requirement of anions. While the solution behavior of 3, with nitrate, is similar to complexes studied earlier, complexes with pseudohalides exhibit new solution behavior. (C) 2002 Elsevier Science Ltd. All rights reserved.

A dynamical instability due to fluid–wall coupling lowers the transition Reynolds number in the flow through a flexible tube

A flow-induced instability in a tube with flexible walls is studied experimentally. Tubes of diameter 0.8 and 1.2 mm are cast in polydimethylsiloxane (PDMS) polymer gels, and the catalyst concentration in these gels is varied to obtain shear modulus in the range 17–550 kPa. A pressure drop between the inlet and outlet of the tube is used to drive fluid flow, and the friction factor $f$ is measured as a function of the Reynolds number $Re$. From these measurements, it is found that the laminar flow becomes unstable, and there is a transition to a more complicated flow profile, for Reynolds numbers as low as 500 for the softest gels used here. The nature of the $f$–$Re$ curves is also qualitatively different from that in the flow past rigid tubes; in contrast to the discontinuous increase in the friction factor at transition in a rigid tube, it is found that there is a continuous increase in the friction factor from the laminar value of $16\ensuremath{/} Re$ in a flexible tube. The onset of transition is also detected by a dye-stream method, where a stream of dye is injected into the centre of the tube. It is found that there is a continuous increase of the amplitude of perturbations at the onset of transition in a flexible tube, in contrast to the abrupt disruption of the dye stream at transition in a rigid tube. There are oscillations in the wall of the tube at the onset of transition, which is detected from the laser scattering off the walls of the tube. This indicates that the coupling between the fluid stresses and the elastic stresses in the wall results in an instability of the laminar flow.

Stability of the flow of a fluid through a flexible tube at high Reynolds number

The stability of the Hagen-Poiseuille flow of a Newtonian fluid in a tube of radius R surrounded by an incompressible viscoelastic medium of radius R < r < HR is analysed in the high Reynolds number regime. The dimensionless numbers that affect the fluid flow are the Reynolds number Re = (ρVR / η), the ratio of the viscosities of the wall and fluid ηr = (ηs/η), the ratio of radii H and the dimensionless velocity Γ = (ρV2/G)1/2. Here ρ is the density of the fluid, G is the coefficient of elasticity of the wall and Vis the maximum fluid velocity at the centre of the tube. In the high Reynolds number regime, an asymptotic expansion in the small parameter ε = (1/Re) is employed. In the leading approximation, the viscous effects are neglected and there is a balance between the inertial stresses in the fluid and the elastic stresses in the medium. There are multiple solutions for the leading-order growth rate do), all of which are imaginary, indicating that the fluctuations are neutrally stable, since there is no viscous dissipation of energy or transfer of energy from the mean flow to the fluctruations due to the Reynolds strees. There is an O(ε1/2) correction to the growth rate, s(1), due to the presence of a wall layer of thickness ε1/2R where the viscous stresses are O(ε1/2) smaller than the inertial stresses. An energy balance analysis indicates that the transfer of energy from the mean flow to the fluctuations due to the Reynolds stress in the wall layer is exactly cancelled by an opposite transfer of equal magnitude due to the deformation work done at the interface, and there is no net transfer from the mean flow to the fluctuations. Consequently, the fluctuations are stabilized by the viscous dissipation in the wall layer, and the real part of s(1) is negative. However, there are certain values of Γ and wavenumber k where s(l) = 0. At these points, the wail layer amplitude becomes zero because the tangential velocity boundary condition is identically satisfied by the inviscid flow solution. The real part of the O(ε) correction to the growth rate s(2) turns out to be negative at these points, indicating a small stabilizing effect due to the dissipation in the bulk of the fluid and the wall material. It is found that the minimum value of s(2) increases [is proportional to] (H − 1)−2 for (H − 1) [double less-than sign] 1 (thickness of wall much less than the tube radius), and decreases [is proportional to] (H−4 for H [dbl greater-than sign] 1. The damping rate for the inviscid modes is smaller than that for the viscous wall and centre modes in a rigid tube, which have been determined previously using a singular perturbation analysis. Therefore, these are the most unstable modes in the flow through a flexible tube.

A Compliant Mechanism Kit with Flexible Beams and Connectors

We present the concept, prototypes, and an optimal design method for a compliant mechanism kit as a parallel to the kits available for rigid-body mechanisms. The kit consists of flexible beams and connectors that can be easily hand-assembled using snap fits. It enables users, using their creativity and mechanics intuition, to quickly realize a compliant mechanism. The mechanisms assembled in this manner accurately capture the essential behavior of the topology, shape, size and material aspects and thereby can lead the way for a real compliant mechanism for practical use. Also described in this paper are the design of the connector to which flexible beams can be added in eight different directions; and prototyping of the spring steel connectors as well as beams using wire-cut electro discharge machining. It is noted in this paper that the concept of the kit also resolves a discrepancy in the finite element (FE) modeling of beam-based compliant mechanisms. The discrepancy arises when two or more beams are joining at one point and thus leading to increased stiffness. After resolving this discrepancy, this work extends the topology optimization to automatically generate designs that can be assembled with the kit. Thus, the kit and the accompanying analysis and optimal synthesis procedures comprise a self-contained educational as well as a research and pragmatic toolset for compliant mechanisms. The paper also illustrates how human creativity finds new ways of using the kit beyond the original intended use and how it is useful even for a novice to design compliant mechanisms.

Design and Implementation of a Flexible and Memory Efficient Operating System for Sensor Nodes

Sensor network nodes exhibit characteristics of both embedded systems and general-purpose systems.A sensor network operating system is a kind of embedded operating system, but unlike a typical embedded operating system, sensor network operatin g system may not be real time, and is constrained by memory and energy constraints. Most sensor network operating systems are based on event-driven approach. Event-driven approach is efficient in terms of time and space.Also this approach does not require a separate stack for each execution context. But using this model, it is difficult to implement long running tasks, like cryptographic operations. A thread based computation requires a separate stack for each execution context, and is less efficient in terms of time and space. In this paper, we propose a thread based execution model that uses only a fixed number of stacks. In this execution model, the number of stacks at each priority level are fixed. It minimizes the stack requirement for multi-threading environment and at the same time provides ease of programming. We give an implementation of this model in Contiki OS by separating thread implementation from protothread implementation completely. We have tested our OS by implementing a clock synchronization protocol using it.