182 research outputs found
It is theoretically possible to avoid misfolding into non-covalent lasso entanglements using small molecule drugs
A novel class of protein misfolding characterized by either the formation of non-native noncovalent lasso entanglements in the misfolded structure or loss of native entanglements has been predicted to exist and found circumstantial support through biochemical assays and limited-proteolysis mass spectrometry data. Here, we examine whether it is possible to design small molecule compounds that can bind to specific folding intermediates and thereby avoid these misfolded states in computer simulations under idealized conditions (perfect drug-binding specificity, zero promiscuity, and a smooth energy landscape). Studying two proteins, type III chloramphenicol acetyltransferase (CAT-III) and D-alanyl-D-alanine ligase B (DDLB), that were previously suggested to form soluble misfolded states through a mechanism involving a failure-to-form of native entanglements, we explore two different drug design strategies using coarse-grained structure-based models. The first strategy, in which the native entanglement is stabilized by drug binding, failed to decrease misfolding because it formed an alternative entanglement at a nearby region. The second strategy, in which a small molecule was designed to bind to a non-native tertiary structure and thereby destabilize the native entanglement, succeeded in decreasing misfolding and increasing the native state population. This strategy worked because destabilizing the entanglement loop provided more time for the threading segment to position itself correctly to be wrapped by the loop to form the native entanglement. Further, we computationally identified several FDA-approved drugs with the potential to bind these intermediate states and rescue misfolding in these proteins. This study suggests it is possible for small molecule drugs to prevent protein misfolding of this type
How accurate are polymer models in the analysis of Forster resonance energy transfer experiments on proteins?
Single molecule Forster resonance energy transfer (FRET) experiments are used
to infer the properties of the denatured state ensemble (DSE) of proteins. From
the measured average FRET efficiency, , the distance distribution P(R) is
inferred by assuming that the DSE can be described as a polymer. The single
parameter in the appropriate polymer model (Gaussian chain, Wormlike chain, or
Self-avoiding walk) for P(R) is determined by equating the calculated and
measured . In order to assess the accuracy of this "standard procedure," we
consider the generalized Rouse model (GRM), whose properties [ and P(R)] can
be analytically computed, and the Molecular Transfer Model for protein L for
which accurate simulations can be carried out as a function of guanadinium
hydrochloride (GdmCl) concentration. Using the precisely computed for the
GRM and protein L, we infer P(R) using the standard procedure. We find that the
mean end-to-end distance can be accurately inferred (less than 10% relative
error) using and polymer models for P(R). However, the value extracted for
the radius of gyration (Rg) and the persistence length (lp) are less accurate.
The relative error in the inferred R-g and lp, with respect to the exact
values, can be as large as 25% at the highest GdmCl concentration. We propose a
self-consistency test, requiring measurements of by attaching dyes to
different residues in the protein, to assess the validity of describing DSE
using the Gaussian model. Application of the self-consistency test to the GRM
shows that even for this simple model the Gaussian P(R) is inadequate. Analysis
of experimental data of FRET efficiencies for the cold shock protein shows that
at there are significant deviations in the DSE P(R) from the Gaussian model.Comment: 31 pages, 9 figure
Influence of Nanoparticle Size and Shape on Oligomer Formation of an Amyloidogenic Peptide
Understanding the influence of macromolecular crowding and nanoparticles on
the formation of in-register -sheets, the primary structural component
of amyloid fibrils, is a first step towards describing \emph{in vivo} protein
aggregation and interactions between synthetic materials and proteins. Using
all atom molecular simulations in implicit solvent we illustrate the effects of
nanoparticle size, shape, and volume fraction on oligomer formation of an
amyloidogenic peptide from the transthyretin protein. Surprisingly, we find
that inert spherical crowding particles destabilize in-register -sheets
formed by dimers while stabilizing -sheets comprised of trimers and
tetramers. As the radius of the nanoparticle increases crowding effects
decrease, implying smaller crowding particles have the largest influence on the
earliest amyloid species. We explain these results using a theory based on the
depletion effect. Finally, we show that spherocylindrical crowders destabilize
the ordered -sheet dimer to a greater extent than spherical crowders,
which underscores the influence of nanoparticle shape on protein aggregation
Delivery of Dark Material to Vesta via Carbonaceous Chondritic Impacts
NASA's Dawn spacecraft observations of asteroid (4) Vesta reveal a surface
with the highest albedo and color variation of any asteroid we have observed so
far. Terrains rich in low albedo dark material (DM) have been identified using
Dawn Framing Camera (FC) 0.75 {\mu}m filter images in several geologic
settings: associated with impact craters (in the ejecta blanket material and/or
on the crater walls and rims); as flow-like deposits or rays commonly
associated with topographic highs; and as dark spots (likely secondary impacts)
nearby impact craters. This DM could be a relic of ancient volcanic activity or
exogenic in origin. We report that the majority of the spectra of DM are
similar to carbonaceous chondrite meteorites mixed with materials indigenous to
Vesta. Using high-resolution seven color images we compared DM color properties
(albedo, band depth) with laboratory measurements of possible analog materials.
Band depth and albedo of DM are identical to those of carbonaceous chondrite
xenolith-rich howardite Mt. Pratt (PRA) 04401. Laboratory mixtures of Murchison
CM2 carbonaceous chondrite and basaltic eucrite Millbillillie also show band
depth and albedo affinity to DM. Modeling of carbonaceous chondrite abundance
in DM (1-6 vol%) is consistent with howardite meteorites. We find no evidence
for large-scale volcanism (exposed dikes/pyroclastic falls) as the source of
DM. Our modeling efforts using impact crater scaling laws and numerical models
of ejecta reaccretion suggest the delivery and emplacement of this DM on Vesta
during the formation of the ~400 km Veneneia basin by a low-velocity (<2
km/sec) carbonaceous impactor. This discovery is important because it
strengthens the long-held idea that primitive bodies are the source of carbon
and probably volatiles in the early Solar System.Comment: Icarus (Accepted) Pages: 58 Figures: 15 Tables:
Hubble Space Telescope Spectroscopy of V471 Tauri: Oversized K Star, Paradoxical White Dwarf
We have used the GHRS onboard the HST to obtain Lyman-alpha spectra of the
hot white-dwarf (WD) component of the short-period eclipsing DA+dK2
pre-cataclysmic binary V471 Tauri, a member of the Hyades star cluster. Radial
velocities of the WD, combined with ground-based measurements of the dK
velocities, eclipse timings, and a determination of the dK star's rotational
velocity, yield dynamical masses for the components of M(WD)=0.84 and
M(dK)=0.93 Msun. Model-atmosphere fitting of the Ly-alpha profile provides the
effective temperature (34,500 K) and surface gravity (log g=8.3) of the WD. The
radius of the dK component is 18% larger than that of a normal Hyades dwarf of
the same mass. This expansion is attributed to the extensive coverage of the
surface by starspots, causing the star to expand in response. The WD radius,
determined from a radiometric analysis and from eclipse ingress timings, is
0.0107 Rsun. The position of the star in the M-R plane is in full accord with
theory for a degenerate CO WD. The high temperature and mass of the WD present
an evolutionary paradox: the WD is the most massive known in the Hyades, but
also the hottest and youngest. We suggest that the explanation is that the WD
is indeed very young, and is descended from a triple consisting of a blue
straggler and a more-distant dK companion. We estimate that the common-envelope
efficiency parameter, alpha_CE, was of order 0.3-1.0, in good agreement with
recent hydrodynamical simulations.Comment: Astrophysical Journal, in press. 34 text pages, 8 figure
Identifying the science and technology dimensions of emerging public policy issues through horizon scanning
Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security.Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security
Escherichia coli O157 Exposure in Wyoming and Seattle: Serologic Evidence of Rural Risk
We tested the hypothesis that rural populations have increased exposure to Escherichia coli O157:H7. We measured circulating antibodies against the O157 lipopolysaccharide in rural Wyoming residents and in blood donors from Casper, Wyoming, and Seattle, Washington, by enzyme immunoassay (EIA). EIA readings were compared by analysis of variance and the least squares difference multiple comparison procedure. Rural Wyoming residents had higher antibody levels to O157 LPS than did Casper donors, who, in turn, had higher levels than did Seattle donors (respective least squares means: 0.356, 0.328, and 0.310; p<0.05, Seattle vs. Casper, p<0.001, rural Wyoming vs. either city). Lower age was significantly correlated with EIA scores; gender; and, in rural Wyoming, history of bloody diarrhea, town, duration of residence, and use of nontreated water at home were not significantly correlated. These data suggest that rural populations are more exposed to E. coli O157:H7 than urban populations
Synchrotron X-Ray Scattering as a Tool for Characterising Catalysts on Multiple Length Scales
Is intramedullary nailing more effective than non-operative treatment in adults with displaced middle-third clavicle fractures?
Search for exotic resonances decaying into WZ/ZZ in pp collisions at √s=7 TeV
Journal of High Energy Physics 2013.2 (2013): 036 reproduced by permission of Scuola Internazionale Superiore di Studi Avanzati (SISSA)Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAMA search for new exotic particles decaying to the VZ final state is performed, where V is either a W or a Z boson decaying into two overlapping jets and the Z decays into a pair of electrons, muons or neutrinos. The analysis uses a data sample of pp collisions corresponding to an integrated luminosity of 5 fb-1 collected by the CMS experiment at the LHC at √s=7 TeV in 2011. No significant excess is observed in the mass distribution of the VZ candidates compared with the background expectation from standard model processes. Model-dependent upper limits at the 95% confidence level are set on the product of the cross section times the branching fraction of hypothetical particles decaying to the VZ final state as a function of mass. Sequential standard model W′ bosons with masses between 700 and 940 GeV are excluded. In the Randall-Sundrum model for graviton resonances with a coupling parameter of 0.05, masses between 750 and 880 GeV are also exclude
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