scholarly journals Molecular aspects of multivalent engagement between Syk and FcεRIγ

2018 ◽  
Author(s):  
Timothy Travers ◽  
William Kanagy ◽  
Elton Jhamba ◽  
Byron Goldstein ◽  
Diane S. Lidke ◽  
...  
Keyword(s):  
Computational Models ◽  
Md Simulations ◽  
Immune Recognition ◽  
Chain Polymer ◽  
Sh2 Domains ◽  
Model Predictions ◽  
Polymer Models ◽  
Molecular Aspects ◽  
Binding Orientations ◽  
The Impact

ABSTRACTSyk/Zap70 family kinases are essential for signaling via multichain immune-recognition receptors such as the tetrameric (αβγ2) FcεRI The simplest model assumes that Syk activation occurs through cis binding of its tandem SH2 domains to dual phosphotyrosines within immunoreceptor tyrosine-based activation motifs of individual γ chains. In this model, Syk activity is modulated by phosphorylation occurring between adjacent Syk molecules docked on γ homodimers and by Lyn molecules bound to FcεRIβ. However, the mechanistic details of Syk docking on γ homodimers are not fully resolved, particularly the possibility of trans binding orientations and the impact of Y130 autophosphorylation within Syk interdomain A. Analytical modeling shows that multivalent interactions lead to increased WT Syk cis-oriented binding by three orders of magnitude. Molecular dynamics (MD) simulations show increased inter-SH2 flexibility in a Y130E phosphomimetic form of Syk, associated with reduced overall helicity of interdomain A. Hybrid MD/worm-like chain polymer models show that the Y130E substitution reduces cis binding of Syk. We report computational models and estimates of relative binding for all possible cis and trans 2:2 Syk:FcεRIγ complexes. Calcium imaging experiments confirm model predictions that cis binding of WT Syk is strongly preferred for efficient signaling, while trans conformations trigger weak but measurable responses.

scholarly journals Combinatorial diversity of Syk recruitment driven by its multivalent engagement with FcεRIγ

2019 ◽  
Vol 30 (17) ◽  
pp. 2331-2347 ◽  
Author(s):  
Timothy Travers ◽  
William K. Kanagy ◽  
Rachael A. Mansbach ◽  
Elton Jhamba ◽  
Cedric Cleyrat ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Live Cell Imaging ◽  
Full Range ◽  
Immune Recognition ◽  
Chain Polymer ◽  
Sh2 Domains ◽  
Relative Binding ◽  
Model Predictions ◽  
Cis And Trans ◽  
Signaling Efficiency

Syk/Zap70 family kinases are essential for signaling via multichain immune-recognition receptors such as tetrameric (αβγ2) FcεRI. Syk activation is generally attributed to cis binding of its tandem SH2 domains to dual phosphotyrosines within FcεRIγ-ITAMs (immunoreceptor tyrosine-based activation motifs). However, the mechanistic details of Syk docking on γ homodimers are unresolved. Here, we estimate that multivalent interactions for WT Syk improve cis-oriented binding by three orders of magnitude. We applied molecular dynamics (MD), hybrid MD/worm-like chain polymer modeling, and live cell imaging to evaluate relative binding and signaling output for all possible cis and trans Syk–FcεRIγ configurations. Syk binding is likely modulated during signaling by autophosphorylation on Y130 in interdomain A, since a Y130E phosphomimetic form of Syk is predicted to lead to reduced helicity of interdomain A and alter Syk’s bias for cis binding. Experiments in reconstituted γ-KO cells, whose γ subunits are linked by disulfide bonds, as well as in cells expressing monomeric ITAM or hemITAM γ-chimeras, support model predictions that short distances between γ ITAM pairs are required for trans docking. We propose that the full range of docking configurations improves signaling efficiency by expanding the combinatorial possibilities for Syk recruitment, particularly under conditions of incomplete ITAM phosphorylation.

Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

2019 ◽  
Vol 25 (7) ◽  
pp. 750-773 ◽  
Author(s):  
Pabitra Narayan Samanta ◽  
Supratik Kar ◽  
Jerzy Leszczynski
Keyword(s):  
Drug Targets ◽  
Biological Activities ◽  
Scoring Function ◽  
Md Simulations ◽  
Energy Calculation ◽  
Binding Modes ◽  
Macromolecular Systems ◽  
In Silico Modeling ◽  
Mathematical Algorithms ◽  
The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

scholarly journals Evaluation of the impact of compliance of precast discs of overlapping on the work of the frame of a multi-storey building

2019 ◽  
Vol 97 ◽  
pp. 04022
Author(s):  
Nikolay Trekin ◽  
Emil Kodysh ◽  
Alexander Bybka ◽  
Alexander Yamalov ◽  
Nikita Konkov
Keyword(s):  
Economic Performance ◽  
Computational Models ◽  
Precast Concrete ◽  
Building Frames ◽  
Frame Building ◽  
Numerical Studies ◽  
Frame Buildings ◽  
The Impact ◽  
Structural Solutions ◽  
Storey Building

The article provides an analysis and justification of the need to take into account the compliance of discs of overlapping and coatings when calculating frames from precast concrete structures. Previously conducted full-scale experiments showed that the rigidity of the precast overlapping with full filling of the seams, in comparison with the monolithic overlapping, decreases by 3-15 times due to the ductility of the joints. The use of refined computational models of structural solutions for frames, which take into account the compliance of the conjugations of elements, makes it possible to trace possible redistribution of efforts. Such an approach when reconstructing, it is possible to optimally select and calculate the enforcement of structure, and on new designing, to increase reliability and / or improve the economic performance of frame buildings. According to the results of analytical studies, formulas were adopted for the parameters that allow one to take into account the overall compliance of overlapping disks and coatings in computational models of building frames. Numerical studies on the computational model of a frame building made it possible to evaluate the effect of accounting for compliance on the stress-strain state of a multi-storey frame.

scholarly journals Evaluation of a Coupled Model to Predict the Impact of Adaptive Behaviour in the Thermal Sensation of Occupants of Naturally Ventilated Buildings in Warm-Humid Regions

2020 ◽  
Vol 13 (1) ◽  
pp. 255
Author(s):  
Luciano C. de Faria ◽  
Marcelo A. Romero ◽  
Lúcia F. S. Pirró
Keyword(s):  
Computational Models ◽  
Thermal Sensation ◽  
Coupled Model ◽  
Adaptive Behaviour ◽  
Humid Climate ◽  
Clothing Insulation ◽  
Tropical Regions ◽  
Naturally Ventilated Buildings ◽  
Adaptive Behaviours ◽  
The Impact

Improving indoor environment quality and making urban centres in tropical regions more sustainable has become a challenge for which computational models for the prediction of thermal sensation for naturally ventilated buildings (NVBs) have major role to play. This work performed analysis on thermal sensation for non-residential NVBs located in Brazilian tropical warm-humid climate and tested the effectiveness of suggested adaptive behaviours to mitigate warm thermal sensation. The research method utilized transient computational fluid dynamics models coupled with a dynamic model for human thermophysiology to predict thermal sensation. The calculated results were validated with comparison with benchmark values from questionnaires and from field measurements. The calculated results for dynamic thermal sensation (DTS) seven-point scale showed higher agreement with the thermal sensation vote than with the predicted mean vote. The test for the suggested adaptive behaviours considered reducing clothing insulation values from 0.18 to 0.32 clo (reducing DTS from 0.1 to 0.9), increasing the air speed in 0.9 m/s (reducing DTS from 0.1 to 0.9), and applying both suggestions together (reducing DTS from 0.1 to 1.3) for five scenarios with operative temperatures spanning 34.5–24.0 °C. Results quantified the tested adaptive behaviours’ efficiency showing applicability to improve thermal sensation from slightly-warm to neutral.

scholarly journals Braided composite stent for peripheral vascular applications

2020 ◽  
Vol 9 (1) ◽  
pp. 1137-1146
Author(s):  
Qingli Zheng ◽  
Pengfei Dong ◽  
Zhiqiang Li ◽  
Ying Lv ◽  
Meiwen An ◽  
...  
Keyword(s):  
Computational Models ◽  
Surface Coverage ◽  
Mechanical Performance ◽  
Wire Diameter ◽  
Orthogonal Experimental Design ◽  
Braided Composite ◽  
Nitinol Wire ◽  
Radial Strength ◽  
Braiding Angle ◽  
The Impact

AbstractBraided composite stent (BCS), woven with nitinol wires and polyethylene terephthalate (PET) strips, provides a hybrid design of stent. The mechanical performance of this novel stent has not been fully investigated yet. In this work, the influence of five main design factors (number of nitinol wires, braiding angle, diameter of nitinol wire, thickness and stiffness of the PET strip) on the surface coverage, radial strength, and flexibility of the BCS were systematically studied using computational models. The orthogonal experimental design was adopted to quantitatively analyze the sensitivity of multiple factors using the minimal number of study cases. Results have shown that the nitinol wire diameter and the braiding angle are two most important factors determining the mechanical performance of the BCS. A larger nitinol wire diameter led to a larger radial strength and less flexibility of the BCS. A larger braiding angle could provide a larger radial strength and better flexibility. In addition, the impact of the braiding angle decreased when the stent underwent a large deformation. At the same time, the impact of the PET strips increased due to the interaction with nitinol wires. Moreover, the number of PET strips played an important role in the surface coverage. This study could help understand the mechanical performance of BCS stent and provides guidance on the optimal design of the stent targeting less complications.

scholarly journals Structural genomics approach to investigate deleterious impact of nsSNPs in conserved telomere maintenance component 1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Arunabh Choudhury ◽  
Taj Mohammad ◽  
Nikhil Samarth ◽  
Afzal Hussain ◽  
Md. Tabish Rehman ◽  
...  
Keyword(s):  
Noncovalent Interactions ◽  
Md Simulations ◽  
Telomere Maintenance ◽  
Nucleotide Polymorphisms ◽  
Telomeric Dna ◽  
Congenital Diseases ◽  
Ob Fold ◽  
Significant Conformational Change ◽  
The Stability ◽  
The Impact

AbstractConserved telomere maintenance component 1 (CTC1) is an important component of the CST (CTC1-STN1-TEN1) complex, involved in maintaining the stability of telomeric DNA. Several non-synonymous single-nucleotide polymorphisms (nsSNPs) in CTC1 have been reported to cause Coats plus syndrome and Dyskeratosis congenital diseases. Here, we have performed sequence and structure analyses of nsSNPs of CTC1 using state-of-the-art computational methods. The structure-based study focuses on the C-terminal OB-fold region of CTC1. There are 11 pathogenic mutations identified, and detailed structural analyses were performed. These mutations cause a significant disruption of noncovalent interactions, which may be a possible reason for CTC1 instability and consequent diseases. To see the impact of such mutations on the protein conformation, all-atom molecular dynamics (MD) simulations of CTC1-wild-type (WT) and two of the selected mutations, R806C and R806L for 200 ns, were carried out. A significant conformational change in the structure of the R806C mutant was observed. This study provides a valuable direction to understand the molecular basis of CTC1 dysfunction in disease progression, including Coats plus syndrome.

The Impact of an Improved Flaw Model on a Pressurized Thermal Shock Evaluation

2002 ◽  
Author(s):  
T. L. Dickson ◽  
F. A. Simonen
Keyword(s):  
Thermal Shock ◽  
Computational Models ◽  
The United States ◽  
Pressure Vessels ◽  
Pressurized Water ◽  
Evaluation Program ◽  
Pressurized Thermal Shock ◽  
Computational Methodology ◽  
The Impact ◽  
Flaw Characterization

The current regulations for pressurized thermal shock (PTS) were derived from computational models that were developed in the early-mid 1980s. The computational models utilized in the 1980s conservatively postulated that all fabrication flaws in reactor pressure vessels (RPVs) were inner-surface breaking flaws. It was recognized at that time that flaw-related data had the greatest level of uncertainty of the inputs required for the probabilistic-based PTS evaluations. To reduce this uncertainty, the United States Nuclear Regulatory Commission (USNRC) has in the past few years supported research at Pacific Northwest National Laboratory (PNNL) to perform extensive nondestructive and destructive examination of actual RPV materials. Such measurements have been used to characterize the number, size, and location of flaws in various types of welds and the base metal used to fabricate RPVs. The USNRC initiated a comprehensive project in 1999 to re-evaluate the current PTS regulations. The objective of the PTS Re-evaluation program has been to incorporate advancements and refinements in relevant technologies (associated with the physics of PTS events) that have been developed since the current regulations were derived. There have been significant improvements in the computational models for thermal hydraulics, probabilistic risk assessment (PRA), human reliability analysis (HRA), materials embrittlement effects on fracture toughness, and fracture mechanics methodology. However, the single largest advancement has been the development of a technical basis for the characterization of fabrication-induced flaws. The USNRC PTS-Revaluation program is ongoing and is expected to be completed in 2002. As part of the PTS Re-evaluation program, the updated risk-informed computational methodology as implemented into the FAVOR (Fracture Analysis of Vessels: Oak Ridge) computer code, including the improved PNNL flaw characterization, was recently applied to a domestic commercial pressurized water reactor (PWR). The objective of this paper is to apply the same updated computational methodology to the same PWR, except utilizing the 1980s flaw model, to isolate the impact of the improved PNNL flaw characterization on the PTS analysis results. For this particular PWR, the improved PNNL flaw characterization significantly reduced the frequency of RPV failure, i.e., by between one and two orders of magnitude.

Impact of random soil properties on stress–strain response

2004 ◽  
Vol 41 (2) ◽  
pp. 351-355 ◽  
Author(s):  
Dieter Stolle ◽  
Peijun Guo ◽  
Gabriel Sedran
Keyword(s):  
Soil Properties ◽  
Constitutive Modelling ◽  
Soil Parameters ◽  
Strain Response ◽  
Constitutive Behaviour ◽  
Stress Strain ◽  
Deterministic Analysis ◽  
Model Predictions ◽  
Random Variability ◽  
The Impact

This paper analyzes the impact of natural random variation of soil properties on the constitutive modelling of geomaterial behaviour. A theoretical framework for accommodating variation in soil properties is presented. The framework is then used to examine the consequence of parameter variability on stress–strain relations. An important observation is that average soil parameters from a series of tests on small specimens, in which density of the specimens varies randomly, do not necessarily reflect the average constitutive behaviour of soil. Model predictions are shown to be consistent with the experimental data.Key words: random variability, deterministic analysis, soil parameters, constitutive model.

Stereoscopically Observed Deformations of a Compliant Abdominal Aortic Aneurysm Model

2011 ◽  
Vol 133 (11) ◽  
Author(s):  
Clark A. Meyer ◽  
Eric Bertrand ◽  
Olivier Boiron ◽  
Valérie Deplano
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Computational Models ◽  
Imaging System ◽  
Strain Differences ◽  
Cyclic Strain ◽  
Experimental Models ◽  
Body Motion ◽  
Abdominal Aortic ◽  
The Impact

A new experimental setup has been implemented to precisely measure the deformations of an entire model abdominal aortic aneurysm (AAA). This setup addresses a gap between the computational and experimental models of AAA that have aimed at improving the limited understanding of aneurysm development and rupture. The experimental validation of the deformations from computational approaches has been limited by a lack of consideration of the large and varied deformations that AAAs undergo in response to physiologic flow and pressure. To address the issue of experimentally validating these calculated deformations, a stereoscopic imaging system utilizing two cameras was constructed to measure model aneurysm displacement in response to pressurization. The three model shapes, consisting of a healthy aorta, an AAA with bifurcation, and an AAA without bifurcation, were also evaluated with computational solid mechanical modeling using finite elements to assess the impact of differences between material properties and for comparison against the experimental inflations. The device demonstrated adequate accuracy (surface points were located to within 0.07 mm) for capturing local variation while allowing the full length of the aneurysm sac to be observed at once. The experimental model AAA demonstrated realistic aneurysm behavior by having cyclic strains consistent with reported clinical observations between pressures 80 and 120 mm Hg. These strains are 1–2%, and the local spatial variations in experimental strain were less than predicted by the computational models. The three different models demonstrated that the asymmetric bifurcation creates displacement differences but not cyclic strain differences within the aneurysm sac. The technique and device captured regional variations of strain that are unobservable with diameter measures alone. It also allowed the calculation of local strain and removed rigid body motion effects on the strain calculation. The results of the computations show that an asymmetric aortic bifurcation created displacement differences but not cyclic strain differences within the aneurysm sac.

scholarly journals Structural Properties of G,T-Parallel Duplexes

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Anna Aviñó ◽  
Elena Cubero ◽  
Raimundo Gargallo ◽  
Carlos González ◽  
Modesto Orozco ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Properties ◽  
Theoretical Calculations ◽  
Md Simulations ◽  
Theoretical Studies ◽  
Duplex Structure ◽  
Strong Stabilization ◽  
The Stability ◽  
The Impact

The structure of G,T-parallel-stranded duplexes of DNA carrying similar amounts of adenine and guanine residues is studied by means of molecular dynamics (MD) simulations and UV- and CD spectroscopies. In addition the impact of the substitution of adenine by 8-aminoadenine and guanine by 8-aminoguanine is analyzed. The presence of 8-aminoadenine and 8-aminoguanine stabilizes the parallel duplex structure. Binding of these oligonucleotides to their target polypyrimidine sequences to form the corresponding G,T-parallel triplex was not observed. Instead, when unmodified parallel-stranded duplexes were mixed with their polypyrimidine target, an interstrand Watson-Crick duplex was formed. As predicted by theoretical calculations parallel-stranded duplexes carrying 8-aminopurines did not bind to their target. The preference for the parallel-duplex over the Watson-Crick antiparallel duplex is attributed to the strong stabilization of the parallel duplex produced by the 8-aminopurines. Theoretical studies show that the isomorphism of the triads is crucial for the stability of the parallel triplex.

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