28 research outputs found
Enhanced Sampling of Intrinsic Structural Heterogeneity of the BH3-Only Protein Binding Interface of Bcl-xL
Antiapoptotic
Bcl-xL plays central roles in regulating programed
cell death. Partial unfolding of Bcl-xL has been observed at the interface
upon specific binding to the pro-apoptotic BH3-only protein PUMA,
which in turn disrupts the interaction of Bcl-xL with tumor suppressor
p53 and promotes apoptosis. Previous analysis of existing Bcl-xL structures
and atomistic molecular dynamics (MD) simulations have suggested that
substantial intrinsic structure heterogeneity exists at the BH3-only
protein binding interface of Bcl-xL to facilitate its conformational
transitions upon binding. In this study, enhanced sampling is applied
to further characterize the interfacial conformations of unbound Bcl-xL
in explicit solvent. Extensive replica exchange with solute tempering
(REST) simulations, with a total accumulated time of 16 μs,
were able to cover much wider conformational spaces for the interfacial
region of Bcl-xL. The resulting structural ensembles are much better
converged, with local and long-range structural features that are
highly consistent with existing NMR data. These simulations further
demonstrate that the BH3-only protein binding interface of Bcl-xL
is intrinsically disordered and samples many rapidly interconverting
conformations. Intriguingly, all previously observed conformers are
well represented in the unbound structure ensemble. Such intrinsic
structural heterogeneity and flexibility may be critical for Bcl-xL
to undergo partial unfolding induced by PUMA binding, and likely provide
a robust basis that allows Bcl-xL to respond sensitively to binding
of various ligands in cellular signaling and regulation
The forest plots of the comparation between IgAN group and control group.
<p>The forest plots of the comparation between IgAN group and control group.</p
Photoluminescence Mechanism of DNA-Templated Silver Nanoclusters: Coupling between Surface Plasmon and Emitter and Sensing of Lysozyme
DNA-templated
silver nanoclusters (DNA-AgNCs) have now been thrust
into the limelight with their superior optical properties and potential
biological applications. However, the origin of photoluminescence
from DNA-AgNCs still remains unclear. In this work, DNA-AgNCs were
synthesized and the photoluminescence properties as well as the biosensing
applications of the designed DNA-AgNCs were investigated. The photoluminescence
properties of the DNA-AgNCs were studied under three regions of excitation
wavelength based on the UV–visible absorption spectra. It was
deemed that the photoluminescence originated from coupling between
the surface plasmon and the emitter in AgNCs when they were excited
by visible light above 500 nm, and thus the emission wavelength varied
with changing the excitation wavelength. The photoluminescence of
the red-emitting-only AgNCs was the intrinsic fluorescence when excited
from 200 to 400 nm, which was only related to the emitter; but for
two components of blue- and red-emitting AgNCs, the emission wavelength
varied with the excitation wavelength ranging from 300 to 360 nm,
and the photoluminescence was a coupling between the surface plasmon
and the emitter. The photoluminescence was only related to the surface
plasmon when the AgNCs were excited from 400 to 500 nm. Four DNA probes
were designed and each contained two parts: one part was the template
used to synthesize AgNCs and it was same to all, and the other part
was the lysozyme binding DNA (LBD) used to bind lysozyme and two kinds
of LBD were studied. It was deemed that the difference in DNA bases,
sequence, and secondary structure caused the synthesized DNA-AgNCs
to be different in photoluminescence properties and sensing ability
to lysozyme, and the sensing mechanism based on photoluminescence
enhancement was also presented. This work explored the origin of photoluminescence
and the sensing ability of DNA-AgNCs, and is hoped to make a better
understanding of this kind of photoluminescence probe
The forest plots of IgAN group and first-degree relatives group.
<p>The forest plots of IgAN group and first-degree relatives group.</p
The forest plots of the comparation among IgAN group, HSPN group and controls.
<p>The forest plots of the comparation among IgAN group, HSPN group and controls.</p
Aberrant IgA1 Glycosylation in IgA Nephropathy: A Systematic Review
<div><p>Objective</p><p>Galactose-deficient IgA1 was evaluated in patients with IgA nephropathy(IgAN) and controls in order to determine the predictive value of galactose-deficient IgA1 in cases of IgA nephropathy.</p><p>Methods</p><p>PubMed, EMBASE, Cochrane central register of controlled trials, CNKI, CBM disc, and VIP database were searched to identify eligible studies that evaluated a difference in aberrant IgA1 glycosylation in IgAN patients compared with controls. A meta-analysis was conducted to evaluate the impact of galactose-deficient IgA1(Gd-IgA1) levels in different groups.</p><p>Results</p><p>A total of 22 studies (n = 1657) met inclusion criteria. The mean Newcastle-Ottawa Scale (NOS) score was 7.2 and ranged from 6 to 8. The standard mean difference(SMD) in the meta-analysis of 20 studies of the level of Gd-IgA1 in the serum and/or supernatant of cultured cells was higher in the IgAN group compared with healthy controls as well as in those with other renal diseases (SMD = 1.76, 95% CI = 1.18–2.34, P<0.00001; SMD = 1.05, 95% CI = 0.05–2.04, P = 0.04). The data synthesis suggested that IgAN patients had similar levels of serum Gd-IgA1, with no significant differences, compared with first-degree relatives and Henoch-Schonlein purpura nephritis (HSPN) patients (MD = 0.04, 95% CI = 0.00–0.08, P = 0.05; MD = -46.03, 95% CI = -217.70–125.64, P = 0.60). In addition, the combined MD of 5 studies indicated that there were no significant differences in Gd-IgA1 levels among patients with varying severities of IgAN (MD = 0.02, 95% CI = -0.02–0.05, P = 0.28).</p><p>Conclusions</p><p>The pooled evidence suggests that the level of Gd-IgA1 in the serum or supernatant of cultured cells from peripheral blood or tonsils may be a useful biomarker for predicting IgA nephropathy, though the level of Gd-IgA1 was not significantly associated with disease severity.</p></div
Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity
Structural mechanisms
and underlying thermodynamic determinants
of efficient internalization of charged cationic peptides (cell-penetrating
peptides, CPPs) such as TAT, polyarginine, and their variants, into
cells, cellular constructs, and model membrane/lipid bilayers (large
and giant unilamellar or multilamelar vesicles) continue to garner
significant attention. Two widely held views on the translocation
mechanism center on endocytotic and nonendocytotic (diffusive) processes.
Espousing the view of a purely diffusive internalization process (supported
by recent experimental evidence, [Säälik, P.; et al. <i>J. Controlled Release</i> <b>2011</b>, <i>153</i>, 117–125]), we consider the underlying free energetics of
the translocation of a nonaarginine peptide (Arg<sub>9</sub>) into
a model DPPC bilayer. In the case of the Arg<sub>9</sub> cationic
peptide, recent experiments indicate a higher internalization efficiency
of the cyclic structure (cyclic Arg<sub>9</sub>) relative to the linear
conformer. Furthermore, recent all-atom resolution molecular dynamics
simulations of cyclic Arg<sub>9</sub> [Huang, K.; et al. <i>Biophys.
J.</i>, <b>2013</b>, <i>104</i>, 412–420]
suggested a critical stabilizing role of water- and lipid-constituted
pores that form within the bilayer as the charged Arg<sub>9</sub> translocates
deep into the bilayer center. Herein, we use umbrella sampling molecular
dynamics simulations with coarse-grained Martini lipids, polarizable
coarse-grained water, and peptide to explore the dependence of translocation
free energetics on peptide structure and conformation via calculation
of potentials of mean force along preselected reaction paths allowing
and preventing membrane deformations that lead to pore formation.
Within the context of the coarse-grained force fields we employ, we
observe significant barriers for Arg<sub>9</sub> translocation from
bulk aqueous solution to bilayer center. Moreover, we do not find
free-energy minima in the headgroup–water interfacial region,
as observed in simulations using all-atom force fields. The pore-forming
paths systematically predict lower free-energy barriers (ca. 90 kJ/mol
lower) than the non pore-forming paths, again consistent with all-atom
force field simulations. The current force field suggests no preference
for the more compact or covalently cyclic structures upon entering
the bilayer. Decomposition of the PMF into the system’s components
indicates that the dominant stabilizing contribution along the pore-forming
path originates from the membrane as both layers of it deformed due
to the formation of pore. Furthermore, our analysis revealed that
although there is significant entropic stabilization arising from
the enhanced configurational entropy exposing more states as the peptide
moves through the bilayer, the enthalpic loss (as predicted by the
interactions of this coarse-grained model) far outweighs any former
stabilization, thus leading to significant barrier to translocation.
Finally, we observe reduction in the translocation free-energy barrier
for a second Arg<sub>9</sub> entering the bilayer in the presence
of an initial peptide restrained at the center, again, in qualitative
agreement with all-atom force fields
The forest plots of comparison among variable grades of IgAN severity.
<p>The forest plots of comparison among variable grades of IgAN severity.</p