High field magneto-transport in high mobility gated InSb/InAlSb quantum well heterostructures

We present high field magneto-transport data from a range of 30nm wide InSb/InAlSb quantum wells. The low temperature carrier mobility of the samples studied ranged from 18.4 to 39.5 m2V-1s-1 with carrier densities between 1.5x1015 and 3.28x1015 m-2. Room temperature mobilities are reported in excess of 6 m2V-1s-1. It is found that the Landau level broadening decreases with carrier density and beating patterns are observed in the magnetoresistance with non-zero node amplitudes in samples with the narrowest broadening despite the presence of a large g-factor. The beating is attributed to Rashba splitting phenomenon and Rashba coupling parameters are extracted from the difference in spin populations for a range of samples and gate biases. The influence of Landau level broadening and spin-dependent scattering rates on the observation of beating in the Shubnikov-de Haas oscillations is investigated by simulations of the magnetoconductance. Data with non-zero beat node amplitudes are accompanied by asymmetric peaks in the Fourier transform, which are successfully reproduced by introducing a spin-dependent broadening in the simulations. It is found that the low-energy (majority) spin up state suffers more scattering than the high-energy (minority) spin down state and that the absence of beating patterns in the majority of (lower density) samples can be attributed to the same effect when the magnitude of the level broadening is large

ProteinArchitect: Protein Evolution above the Sequence Level

While many authors have discussed models and tools for studying protein evolution at the sequence level, molecular function is usually mediated by complex, higher order features such as independently folding domains and linear motifs that are based on or embedded in a particular arrangment of features such as secondary structure elements, transmembrane domains and regions with intrinsic disorder. This 'protein architecture' can, in its most simplistic representation, be visualized as domain organization cartoons that can be used to compare proteins in terms of the order of their mostly globular domains.Here, we describe a visual approach and a webserver for protein comparison that extend the domain organization cartoon concept. By developing an information-rich, compact visualization of different protein features above the sequence level, potentially related proteins can be compared at the level of propensities for secondary structure, transmembrane domains and intrinsic disorder, in addition to PFAM domains. A public Web server is available at www.proteinarchitect.net, while the code is provided at protarchitect.sourceforge.net.Due to recent advances in sequencing technologies we are now flooded with millions of predicted proteins that await comparative analysis. In many cases, mature tools focused on revealing hits with considerable global or local similarity to well-characterized proteins will not be able to lead us to testable hypotheses about a protein's function, or the function of a particular region. The visual comparison of different types of protein features with ProteinArchitect will be useful when assessing the relevance of similarity search hits, to discover subgroups in protein families and superfamilies, and to understand protein regions with conserved features outside globular regions. Therefore, this approach is likely to help researchers to develop testable hypotheses about a protein's function even if is somewhat distant from the more characterized proteins, by facilitating the discovery of features that are conserved above the sequence level for comparison and further experimental investigation

Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein

Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin precursor protein (MstnPP) has been shown to associate with large molecular weight filamentous inclusions containing the Alzheimer's amyloid beta peptide in sIBM tissue, and MstnPP is upregulated following ER stress. The mechanism for how MstnPP contributes to disease pathogenesis is unknown. Here, we show for the first time that MstnPP is capable of forming amyloid fibrils in vitro. When MstnPP-containing Escherichia coli inclusion bodies are refolded and purified, a proportion of MstnPP spontaneously misfolds into amyloid-like aggregates as characterised by electron microscopy and binding of the amyloid-specific dye thioflavin T. When subjected to a slightly acidic pH and elevated temperature, the aggregates form straight and unbranched amyloid fibrils 15 nm in diameter and also exhibit higher order amyloid structures. Circular dichroism spectroscopy reveals that the amyloid fibrils are dominated by β-sheet and that their formation occurs via a conformational change that occurs at a physiologically relevant temperature. Importantly, MstnPP aggregates and protofibrils have a negative effect on the viability of myoblasts. These novel results show that the myostatin precursor protein is capable of forming amyloid structures in vitro with implications for a role in sIBM pathogenesis

Going beyond Clustering in MD Trajectory Analysis: An Application to Villin Headpiece Folding

Recent advances in computing technology have enabled microsecond long all-atom molecular dynamics (MD) simulations of biological systems. Methods that can distill the salient features of such large trajectories are now urgently needed. Conventional clustering methods used to analyze MD trajectories suffer from various setbacks, namely (i) they are not data driven, (ii) they are unstable to noise and changes in cut-off parameters such as cluster radius and cluster number, and (iii) they do not reduce the dimensionality of the trajectories, and hence are unsuitable for finding collective coordinates. We advocate the application of principal component analysis (PCA) and a non-metric multidimensional scaling (nMDS) method to reduce MD trajectories and overcome the drawbacks of clustering. To illustrate the superiority of nMDS over other methods in reducing data and reproducing salient features, we analyze three complete villin headpiece folding trajectories. Our analysis suggests that the folding process of the villin headpiece is structurally heterogeneous

Integrating Experiment and Theory to Understand TCR-pMHC Dynamics

The conformational dynamism of proteins is well established. Rather than having a single structure, proteins are more accurately described as a conformational ensemble that exists across a rugged energy landscape, where different conformational sub-states interconvert. The interaction between αβ T cell receptors (TCR) and cognate peptide-MHC (pMHC) is no exception, and is a dynamic process that involves substantial conformational change. This review focuses on technological advances that have begun to establish the role of conformational dynamics and dynamic allostery in TCR recognition of the pMHC and the early stages of signaling. We discuss how the marriage of molecular dynamics (MD) simulations with experimental techniques provides us with new ways to dissect and interpret the process of TCR ligation. Notably, application of simulation techniques lags behind other fields, but is predicted to make substantial contributions. Finally, we highlight integrated approaches that are being used to shed light on some of the key outstanding questions in the early events leading to TCR signaling

A Surface-Gated InSb Quantum Well Single Electron Transistor

Single electron charging effects in a surface-gated InSb/AlInSb QW structure are reported. This material, due to its large g-factor and light effective mass, offers considerable advantages over more commonly used materials, such as GaAs, for quantum information processing devices. However, differences in material and device technology result in significant processing challenges. Simple Coulomb blockade and quantised confinement models are considered to explain the observation of conductance oscillations in these structures. The charging energy is found to be comparable with the energy spectrum for single particle states

Tamoxifen Enhances the Hsp90 Molecular Chaperone ATPase Activity

Background: Hsp90 is an essential molecular chaperone that is also a novel anti-cancer drug target. There is growing interest in developing new drugs that modulate Hsp90 activity. Methodology/Principal Findings: Using a virtual screening approach, 4-hydroxytamoxifen, the active metabolite of the anti-estrogen drug tamoxifen, was identified as a putative Hsp90 ligand. Surprisingly, while all drugs targeting Hsp90 inhibit the chaperone ATPase activity, it was found experimentally that 4-hydroxytamoxifen and tamoxifen enhance rather than inhibit Hsp90 ATPase. Conclusions/Significance: Hence, tamoxifen and its metabolite are the first members of a new pharmacological class of Hsp90 activators

Chiminey: Reliable Computing and Data Management Platform in the Cloud

The enabling of scientific experiments that are embarrassingly parallel, long running and data-intensive into a cloud-based execution environment is a desirable, though complex undertaking for many researchers. The management of such virtual environments is cumbersome and not necessarily within the core skill set for scientists and engineers. We present here Chiminey, a software platform that enables researchers to (i) run applications on both traditional high-performance computing and cloud-based computing infrastructures, (ii) handle failure during execution, (iii) curate and visualise execution outputs, (iv) share such data with collaborators or the public, and (v) search for publicly available data.Comment: Preprint, ICSE 201

Protein Folding Database (PFD 2.0): an online environment for the International Foldeomics Consortium

The Protein Folding Database (PFD) is a publicly accessible repository of thermodynamic and kinetic protein folding data. Here we describe the first major revision of this work, featuring extensive restructuring that conforms to standards set out by the recently formed International Foldeomics Consortium. The database now adopts standards for data acquisition, analysis and reporting proposed by the consortium, which will facilitate the comparison of folding rates, energies and structure across diverse sets of proteins. Data can now be easily deposited using a rich set of deposition tools. Enhanced search tools allow sophisticated searching and graphical data analysis affords simple data analysis online. PFD can be accessed freely at

High field magneto-transport in high mobility gated InSb/InAlSb quantum well heterostructures

We present high field magneto-transport data from a range of 30nm wide InSb/InAlSb quantum wells. The low temperature carrier mobility of the samples studied ranged from 18.4 to 39.5 m2V-1s-1 with carrier densities between 1.5x1015 and 3.28x1015 m-2. Room temperature mobilities are reported in excess of 6 m2V-1s-1. It is found that the Landau level broadening decreases with carrier density and beating patterns are observed in the magnetoresistance with non-zero node amplitudes in samples with the narrowest broadening despite the presence of a large g-factor. The beating is attributed to Rashba splitting phenomenon and Rashba coupling parameters are extracted from the difference in spin populations for a range of samples and gate biases. The influence of Landau level broadening and spin-dependent scattering rates on the observation of beating in the Shubnikov-de Haas oscillations is investigated by simulations of the magnetoconductance. Data with non-zero beat node amplitudes are accompanied by asymmetric peaks in the Fourier transform, which are successfully reproduced by introducing a spin-dependent broadening in the simulations. It is found that the low-energy (majority) spin up state suffers more scattering than the high-energy (minority) spin down state and that the absence of beating patterns in the majority of (lower density) samples can be attributed to the same effect when the magnitude of the level broadening is large