21 research outputs found
Influence of Aqueous-Salt Conditions on the Structure and Dynamics of the Monomeric and Novel Dimeric forms of the Alzheimer's A[beta]21-30 protein fragment
The behavior of the Alzheimer's related peptide Aβ is the subject of much study. In typical computational studies the environment local to the peptide is assumed to be pure water; however, in vivo the peptide is found in the extracellular space near the plasma membrane which is rich in ionic species. In this thesis, the hypothesis that the presence of group I/IIA salts will result in increased sampling of disordered structures as well as modify the dynamics of meta-stable structural motifs in the small folding nucleus of the Aβ peptide (Aβ21-30) is examined under a variety of ionic environments and was shown that of the tested salts, CaCl2 (and MgCl2, to a much lesser degree) did increase the propensity for disordered states; while, the group IA salts, KCl and NaCl, had little effect on the secondary structure of the peptide. Further, study of three familial mutations of this peptide region is also performed under aqueous salt-environments to elucidate further mechanistic details of how aqueous salts modify the region's behavior. Finally, as experimental results have highlighted that aggregation rates of the full-length peptide are modified by the presence of CaCl2, this work examines novel dimers states of Aβ21-30 and their stabilities when exposed to CaCl2.Ph.D., Physics -- Drexel University, 201
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A Multifunctional Cosolvent Pair Reveals Molecular Principles of Biomass Deconstruction
Effect of Ionic Aqueous Environments on the Structure and Dynamics of the Aβ<sub>21–30</sub> Fragment: A Molecular-Dynamics Study
The
amyloid β-protein (Aβ) has been implicated in the pathogenesis
of Alzheimer’s disease. The role of the structure and dynamics
of the central Aβ<sub>21–30</sub> decapeptide region
of the full-length Aβ is considered crucial in the aggregation
pathway of Aβ. Here we report results of isobaric–isothermal
(NPT) all-atom explicit water molecular dynamics simulations of the
monomeric form of the wild-type Aβ<sub>21–30</sub> fragment
in aqueous salt environments formed by neurobiologically important
group IA (NaCl, KCl) and group IIA (CaCl<sub>2</sub>, MgCl<sub>2</sub>) salts. Our simulations reveal the existence of salt-specific changes
to secondary structure propensities, lifetimes, hydrogen bonding,
salt-bridge formation, and decapeptide–ion contacts of this
decapeptide. These results suggest that aqueous environments with
the CaCl<sub>2</sub> salt, and to a much lesser extent the MgCl<sub>2</sub> salt, have profound effects by increasing random coil structure
propensities and lifetimes and diminishing intrapeptide hydrogen bonding.
These effects are rationalized in terms of direct cation–decapeptide
contacts and changes to the hydration-shell water molecules. On the
other side of the spectrum, environments with the NaCl and KCl salts
have little influence on the decapeptide’s secondary structure
despite increasing hydrogen bonding, salt-bridge formation, and lifetime
of turn structures. The observed enhancement of open structures by
group IIA may be of importance in the folding and aggregation pathway
of the full-length Aβ
Changes to the Structure and Dynamics in Mutations of Aβ<sub>21–30</sub> Caused by Ions in Solution
The structure and dynamics of the
21–30 fragment of the
amyloid β-protein (Aβ<sub>21–30</sub>) and its
Dutch [Glu22Gln], Arctic [Glu22Gly], and Iowa [Asp23Asn] isoforms
are of considerable importance, as their folding may play an important
role in the pathogenesis of sporadic and familial forms of Alzheimer’s
disease and cerebral amyloid angiopathy. A full understanding of this
pathologic folding in in vivo environments is still elusive. Here
we examine the interactions and effects of two neurobiologically relevant
salts (CaCl<sub>2</sub> and KCl) on the structure and dynamics of
Aβ<sub>21–30</sub> decapeptide monomers containing the
Dutch, Arctic, and Iowa charge-modifying point mutations using isobaric–isothermal
(NPT) explicit water all-atom molecular-dynamics simulations. Measurements
of secondary structure populations, intrapeptide hydrogen bonding,
salt bridging, secondary structure lifetimes, cation–residue
contacts, water–peptide hydrogen bonding, and hydration-shell
water residence times reveal a variety of ion and mutation-dependent
modifications to the decapeptide’s structure and dynamics.
In general, Ca<sup>2+</sup> has the effect of increasing coil-state
populations and lifetimes, modifying the behavior of the decapeptide’s
hydration shell and diminishing intrapeptide hydrogen bonding, while
K<sup>+</sup> is found to diminish coil populations and lifetimes
and, for the case of the Iowa mutant, dramatically increase the decapeptide’s
propensity for β secondary structures. Mutation-dependent effects
highlight the different roles of the Glu22 and Asp23 residues in either
solvating or enhancing turn structures, respectively. Taken together,
our results provide insights into the differential roles of different
ionic species as well as specific effects on the Glu22 and Asp23 residues
of Aβ<sub>21–30</sub> mediated by ion–decapeptide
interactions and the solvent, which could be important interaction
mechanisms relevant to the peptide’s behavior in both in vitro
and in vivo environments
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Temperature-dependent phase behaviour of tetrahydrofuran-water alters solubilization of xylan to improve co-production of furfurals from lignocellulosic biomass
The Stability of a β‑Hairpin Is Altered by Surface–Water Interactions under Confinement
Understanding
protein folding and stability in in vivo confined
environments is a challenging problem from both experimental and computational
points of views. Despite recent insights, an appreciation and complete
understanding of how the solvent influences the structure and stability
of proteins under complex confined environments is still lacking.
Here, using all-atom molecular dynamics simulations in explicit solvent,
we report the effects of confinement on the lifetime of a metastable
β-hairpin structure in the AβÂ(21–30) decapeptide.
Our results show that the values of these lifetimes depend on the
nature of the confining surface, where smooth and rough hydrophobic
confining walls have solvent-mediated stabilizing and destabilizing
effects, respectively. The source of the destabilization found inside
atomically rough confining walls lies in surface–peptide interactions
that break the β-hairpin in this peptide, whereas smooth confining
walls stabilize it by forming well-ordered layers of water that keep
the decapeptide solvated in the inner part of the pore and away from
the surface. In addition, we show that the size of the confining pore
can tune the value of the lifetimes where pore sizes comparable to
the size of the decapeptide have the largest effects
Force-Field Induced Bias in the Structure of Aβ<sub>21–30</sub>: A Comparison of OPLS, AMBER, CHARMM, and GROMOS Force Fields
In
this work we examine the dynamics of an intrinsically disordered
protein fragment of the amyloid β, the Aβ<sub>21–30</sub>, under seven commonly used molecular dynamics force fields (OPLS-AA,
CHARMM27-CMAP, AMBER99, AMBER99SB, AMBER99SB-ILDN, AMBER03, and GROMOS53A6),
and three water models (TIP3P, TIP4P, and SPC/E). We find that the
tested force fields and water models have little effect on the measures
of radii of gyration and solvent accessible surface area (SASA); however,
secondary structure measures and intrapeptide hydrogen-bonding are
significantly modified, with AMBER (99, 99SB, 99SB-ILDN, and 03) and
CHARMM22/27 force-fields readily increasing helical content and the
variety of intrapeptide hydrogen bonds. On the basis of a comparison
between the population of helical and β structures found in
experiments, our data suggest that force fields that suppress the
formation of helical structure might be a better choice to model the
Aβ<sub>21–30</sub> peptide
Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice
Abstract Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood. Here, we used mouse genetics, mechanical loading, and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts. We created and compared the skeletal phenotypes of control Pkd1 flox/+;Wwtr1 flox/+, Pkd1 Oc-cKO , Wwtr1 Oc-cKO , and Pkd1/Wwtr1 Oc-cKO mice to investigate genetic interactions. Consistent with an interaction between polycystins and Wwtr1 in bone in vivo, Pkd1/Wwtr1 Oc-cKO mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1 Oc-cKO or Pkd1 Oc-cKO mice. Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1 Oc-cKO mice compared to either Pkd1 Oc-cKO or Wwtr1 Oc-cKO mice. Pkd1/Wwtr1 Oc-cKO mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1 Oc-cKO or Wwtr1 Oc-cKO mice. Moreover, we found that Pkd1/Wwtr1 Oc-cKO mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of load-induced mechanosensing gene expression compared to control mice. Finally, control mice treated with a small molecule mechanomimetic, MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control. In contrast, Pkd1/Wwtr1 Oc-cKO mice were resistant to the anabolic effects of MS2. These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis
Impact of hydration and temperature history on the structure and dynamics of lignin
Mamontov, Eugene/0000-0002-5684-2675; Smith, Micholas Dean/0000-0002-0777-7539; smith, jeremy c/0000-0002-2978-3227; Parks, Jerry M./0000-0002-3103-9333; Ragauskas, Art/0000-0002-3536-554X; VURAL, DERYA/0000-0002-0120-3024; Sokolov, Alexei/0000-0002-8187-9445; Gainaru, Catalin/0000-0001-8295-6433WOS: 000432567300021The full utilization of plant biomass for the production of energy and novel materials often involves high temperature treatment. Examples include melt spinning of lignin for manufacturing low-cost carbon fiber and the relocalization of lignin to increase the accessibility of cellulose for production of biofuels. These temperature-induced effects arise from poorly understood changes in lignin flexibility. Here, we combine molecular dynamics simulations with neutron scattering and dielectric spectroscopy experiments to probe the dependence of lignin dynamics on hydration and thermal history. We find a dynamical and structural hysteresis: at a given temperature, the lignin molecules are more expanded and their dynamics faster when the lignin is cooled than when heated. The structural hysteresis is more pronounced for dry lignin. The difference in dynamics, however, follows a different trend, it is found to be more significant at high temperatures and high hydration levels. The simulations also reveal syringyl units to be more dynamic than guiacyl. The results provide an atomic-detailed description of lignin dynamics, important for understanding lignin role in plant cell wall mechanics and for rationally improving lignin processing. The lignin glass transition, at which the polymer softens, is lower when lignin is cooled than when heated; therefore extending the cooling phase of processing and shortening the heating phase may offer ways to lower processing costs.Genomic Science Program, Office of Biological and Environmental Research, U. S. Department of Energy (DOE) [FWP ERKP752]; Office of Science of the U. S. Department of EnergyUnited States Department of Energy (DOE) [DE-AC02-05CH11231]; DOEUnited States Department of Energy (DOE) [DE-AC05-00OR22725]; DOE Office of Science, BES Materials Sciences and Engineering DivisionThis research was supported by the Genomic Science Program, Office of Biological and Environmental Research, U. S. Department of Energy (DOE), under Contract FWP ERKP752. CG and APS acknowledge support by the DOE Office of Science, BES Materials Sciences and Engineering Division for the dielectric studies. This research used resources of the National Energy Research Scientific Computing Center, a DOE Office of Science User Facility supported by the Office of Science of the U. S. Department of Energy under Contract No. DE-AC02-05CH11231. This research used resources at the Spallation Neutron Source, a DOE Office of Science User Facility operated by the Oak Ridge National Laboratory, managed by UT-Battelle, LLC, for DOE under Contract DE-AC05-00OR22725