2,589 research outputs found
A Novel Scoring Based Distributed Protein Docking Application to Improve Enrichment
Molecular docking is a computational technique which predicts the binding energy and the preferred binding mode of a ligand to a protein target. Virtual screening is a tool which uses docking to investigate large chemical libraries to identify ligands that bind favorably to a protein target. We have developed a novel scoring based distributed protein docking application to improve enrichment in virtual screening. The application addresses the issue of time and cost of screening in contrast to conventional systematic parallel virtual screening methods in two ways. Firstly, it automates the process of creating and launching multiple independent dockings on a high performance computing cluster. Secondly, it uses a N˙ aive Bayes scoring function to calculate binding energy of un-docked ligands to identify and preferentially dock (Autodock predicted) better binders. The application was tested on four proteins using a library of 10,573 ligands. In all the experiments, (i). 200 of the 1000 best binders are identified after docking only 14% of the chemical library, (ii). 9 or 10 best-binders are identified after docking only 19% of the chemical library, and (iii). no significant enrichment is observed after docking 70% of the chemical library. The results show significant increase in enrichment of potential drug leads in early rounds of virtual screening
Solution Structures of \u3cem\u3eMycobacterium tuberculosis\u3c/em\u3e Thioredoxin C and Models of Intact Thioredoxin System Suggest New Approaches to Inhibitor and Drug Design
Here, we report the NMR solution structures of Mycobacterium tuberculosis (M. tuberculosis) thioredoxin C in both oxidized and reduced states, with discussion of structural changes that occur in going between redox states. The NMR solution structure of the oxidized TrxC corresponds closely to that of the crystal structure, except in the C-terminal region. It appears that crystal packing effects have caused an artifactual shift in the α4 helix in the previously reported crystal structure, compared with the solution structure. On the basis of these TrxC structures, chemical shift mapping, a previously reported crystal structure of the M. tuberculosis thioredoxin reductase (not bound to a Trx) and structures for intermediates in the E. coli thioredoxin catalytic cycle, we have modeled the complete M. tuberculosis thioredoxin system for the various steps in the catalytic cycle. These structures and models reveal pockets at the TrxR/TrxC interface in various steps in the catalytic cycle, which can be targeted in the design of uncompetitive inhibitors as potential anti-mycobacterial agents, or as chemical genetic probes of function
Phenomenology of the Future:The temporality of objects beyond the temporality of inner-time consciousness
Based on a creative use of the phenomenological method, we argue that a close examination of the temporality of objects reveals the future as genuinely open. Without aiming to decide the matter of phenomenological realism, we suggest that this method can be used to investigate the mode of being of objects in their own temporality. By bracketing the anticipatory structure of experience, one can get a sense of objects’ temporality as independent of consciousness. This contribution adds a further voice to the current realism versus idealism debates, but it does so without taking sides. The starting point is neither an analysis of pure consciousness, nor attempts to describe objects in-themselves, but the idea that things can be phenomenologically grasped through the difference between their temporality and our own. By being methodically “open to the future,” one can become aware of the sui generis temporality of objects as different from the temporality shaped by our anticipation
Phenomenology of the Future:The temporality of objects beyond the temporality of inner-time consciousness
Based on a creative use of the phenomenological method, we argue that a close examination of the temporality of objects reveals the future as genuinely open. Without aiming to decide the matter of phenomenological realism, we suggest that this method can be used to investigate the mode of being of objects in their own temporality. By bracketing the anticipatory structure of experience, one can get a sense of objects’ temporality as independent of consciousness. This contribution adds a further voice to the current realism versus idealism debates, but it does so without taking sides. The starting point is neither an analysis of pure consciousness, nor attempts to describe objects in-themselves, but the idea that things can be phenomenologically grasped through the difference between their temporality and our own. By being methodically “open to the future,” one can become aware of the sui generis temporality of objects as different from the temporality shaped by our anticipation
Bound States in the Continuum Realized in the One-Dimensional Two-Particle Hubbard Model with an Impurity
We report a bound state of the one-dimensional two-particle (bosonic or
fermionic) Hubbard model with an impurity potential. This state has the
Bethe-ansatz form, although the model is nonintegrable. Moreover, for a wide
region in parameter space, its energy is located in the continuum band. A
remarkable advantage of this state with respect to similar states in other
systems is the simple analytical form of the wave function and eigenvalue. This
state can be tuned in and out of the continuum continuously.Comment: A semi-exactly solvable model (half of the eigenstates are in the
Bethe form
A Dynamical Model of Binding in Visual Cortex During Incremental Grouping and Search
Binding of visual information is crucial for several perceptual tasks. To incrementally group an object, elements in a space-feature neighborhood need to be bound together starting from an attended location (Roelfsema, TICS, 2005). To perform visual search, candidate locations and cued features must be evaluated conjunctively to retrieve a target (Treisman&Gormican, Psychol Rev, 1988). Despite different requirements on binding, both tasks are solved by the same neural substrate. In a model of perceptual decision-making, we give a mechanistic explanation for how this can be achieved. The architecture consists of a visual cortex module and a higher-order thalamic module. While the cortical module extracts stimulus features across a hierarchy of spatial scales, the thalamic module provides a purely spatial relevance map. Both modules interact bidirectionally to enter locations of task-relevance into thalamus, while allowing integration of context with local features within cortical maps. This integration realizes the model\u27s binding mechanism. It is implemented by pyramidal neurons with dynamical basal and apical compartments performing coincidence detection (Larkum, TINS, 2013). The basal compartment is driven by bottom-up feature information and produces the neuron\u27s output, the apical compartment computes top-down contextual information akin to an interaction skeleton (Roelfsema&Singer, Cereb Cortex, 1998). Apical-basal integration yields an up-modulation in neuron activity binding it to the attended configuration. Gating information from thalamus restricts this integration to task-relevant locations (Saalman&Kastner, Curr Op Neurobiol, 2009). By model simulations, we show how altering the apical compartment\u27s operation regime steers binding to either perform search or incremental grouping
Spontaneous charge carrier localization in extended one-dimensional systems
Charge carrier localization in extended atomic systems has been described
previously as being driven by disorder, point defects or distortions of the
ionic lattice. Here we show for the first time by means of first-principles
computations that charge carriers can spontaneously localize due to a purely
electronic effect in otherwise perfectly ordered structures. Optimally-tuned
range-separated density functional theory and many-body perturbation
calculations within the GW approximation reveal that in trans-polyacetylene and
polythiophene the hole density localizes on a length scale of several
nanometers. This is due to exchange-induced translational symmetry breaking of
the charge density. Ionization potentials, optical absorption peaks, excitonic
binding energies and the optimally-tuned range parameter itself all become
independent of polymer length as it exceeds the critical localization scale.
Moreover, lattice disorder and the formation of a polaron result from the
charge localization in contrast to the traditional view that lattice
distortions precede charge localization. Our results can explain experimental
findings that polarons in conjugated polymers form instantaneously after
exposure to ultrafast light pulses.Comment: 5 pages, 4 figure
Theoretical and Computational Basis for CATNETS - Annual Report Year 3
In this document the developments in defining the computational and theoretical framework for economical resource allocation are described. Accordingly the formal specification of the market mechanisms, bidding strategies of the involved agents and the integration of the market mechanisms into the simulator were refined. --Grid Computing
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